interleukin 17

C Subfamily
CC Subfamily
CXC Subfamily
CX3C Subfamily

Chemokines

gp130 (IL6ST) shared
IL13RA1 shared
IL3RB (CSF2RB) shared
ILRG shared

interleukin 18
interleukin 18 proprotein
interleukin 1 alpha
interleukin 1, alpha proprotein
interleukin 1 beta
interleukin 1, beta proprotein

interleukin 17
interleukin 17b
interleukin 17E
interleukin 17E isoform 1

IL-1 Family /IL-17 Family

interleukin 10
interleukin 19
interleukin 19 isoform 2
interleukin 20
interleukin 22
interleukin 24
interleukin 24 isoform 1
interleukin 28A
interleukin 28B
interleukin 29

IL-10 Family

interferon alpha family, gene 1
interferon, alpha 1
interferon beta
interferon, beta 1
interferon epsilon 1
interferon, epsilon 1
interferon gamma
interferon, gamma
interferon kappa
interferon, kappa
interferon, omega 1

Interferon Family

CSF1 Egf Flt3l
FLT3LG HGF Kitl
KITLG Pdgfa PDGFB
PDGFC Pdgfd PLEKHQ1
VEGF Vegfa VEGFB
VEGFC

PDGF Family

AMH Bmp2 Bmp7
GDF5 Inhba INHBB
INHBC INHBE Tgfb1
TGFB2 TGFB3

TGF-β Family

CD40LG Eda Fasl
FASLG Lta LTB
TNF Tnfsf10 Tnfsf11
TNFSF12 Tnfsf13 TNFSF13B
Tnfsf14 TNFSF18 TNFSF4
TNFSF7 TNFSF8 TNFSF9

TNF Family

INTERLEUKIN 17

LATEST LITERATURE

1: Circulation research, 2010 Sep 2, 275(1-3)
Interleukin-17-Dependent Autoimmunity to Collagen Type V in Atherosclerosis.

[Abstract]Rationale: Considerable evidence shows atherosclerosis to be a chronic inflammatory disease in which immunity to self-antigens contributes to disease progression. We recently identified the collagen type V [col(V)] alpha1(V) chain as a key autoantigen driving the Th17-dependent cellular immunity underlying another chronic inflammatory disease, obliterative bronchiolitis. Because specific induction of alpha1(V) chains has previously been reported in human atheromas, we postulated involvement of col(V) autoimmunity in atherosclerosis. Objective: To determine whether col(V) autoimmunity may be involved in the pathogenesis of atherosclerosis. Methods and Results: Here, we demonstrate Th17-dependent anti-col(V) immunity to be characteristic of atherosclerosis in human coronary artery disease (CAD) patients and in apolipoprotein E-null (ApoE(-/-)) atherosclerotic mice. Responses were alpha1(V)-specific in CAD with variable Th1 pathway involvement. In early atherosclerosis in ApoE(-/-) mice, anti-col(V) immunity was tempered by an interleukin (IL)-10-dependent mechanism. In support of a causal role for col(V) autoimmunity in the pathogenesis of atherosclerosis, col(V) sensitization of ApoE(-/-) mice on a regular chow diet overcame IL-10-mediated inhibition of col(V) autoimmunity, leading to increased atherosclerotic burden in these mice and local accumulation of IL-17-producing cells, particularly in the col(V)-rich adventitia subjacent to the atheromas. Conclusions: These findings establish col(V) as an autoantigen in human CAD and show col(V) autoimmunity to be a consistent feature in atherosclerosis in humans and mice. Furthermore, data are consistent with a causative role for col(V) in the pathogenesis of atherosclerosis.

2: Journal of immunology (Baltimore, Md. : 1950), 2010 Sep 1, 89(9)
Lack of TNFR p55 Results in Heightened Expression of IFN-{gamma} and IL-17 during the Development of Reactive Arthritis.

[Abstract]Reactive arthritis (ReA) is a type of arthritis originating from certain gastrointestinal or genitourinary infections. In previous studies, we reported the development of progressive Yersinia enterocolitica-induced ReA in mice lacking TNFR p55; however, the mechanisms underlying this effect are still uncertain. In this study, we investigated the impact of TNFR p55 deficiency in modulating Ag-specific Th1 and Th17 responses during this arthritogenic process. We found more severe ReA in TNFRp55(-/-) mice compared with their wild-type (WT) counterparts. This effect was accompanied by increased levels of Yersinia LPS in the joints of knockout mice. Analysis of the local cytokine profile revealed greater amounts of IFN-gamma and IL-17 in arthritic joints of TNFRp55(-/-) mice compared with WT mice at day 21 postinfection. Moreover, altered IL-17 and IFN-gamma production was observed in mesenteric and inguinal lymph nodes of Yersinia-infected TNFRp55(-/-) mice, as well as in spleen cells obtained from infected mice and restimulated ex vivo with bacterial Ags. Increased levels of cytokine secretion were associated with a greater frequency of CD4(+)IL-17(+), CD4(+)IFN-gamma(+), and IL-17(+)IFN-gamma(+) cells in TNFRp55(-/-) mice compared with WT mice. Remarkably, Ab-mediated blockade of IL-17 and/or IFN-gamma resulted in reduced joint histological scores in TNFRp55(-/-) mice. A mechanistic analysis revealed the involvement of p40, a common subunit of heterodimeric IL-12 and IL-23, in the generation of augmented IFN-gamma and IL-17 production under TNFR p55 deficiency. Taken together, these data indicate that, in the absence of TNFR p55 signaling, Th1 and Th17 effector cells may act in concert to sustain the inflammatory response in bacterial-induced arthritogenic processes.

3: Journal of immunology (Baltimore, Md. : 1950), 2010 Sep 1, 89(9)
Cutting Edge: Increased IL-17-Secreting T Cells in Children with New-Onset Type 1 Diabetes.

[Abstract]CD4(+)FOXP3(+) regulatory T cells are essential for immune tolerance, and murine studies suggest that their dysfunction can lead to type 1 diabetes (T1D). Human studies assessing regulatory T cell dysfunction in T1D have relied on analysis of FOXP3-expressing cells. Recently, distinct subsets of CD4(+)FOXP3(+) T cells with differing function were identified. Notably, CD45RA(-)CD25(int)FOXP3(low) T cells lack suppressive function and secrete the proinflammatory cytokine IL-17. Therefore, we evaluated whether the relative fractions of CD4(+)FOXP3(+) subsets are altered in new-onset T1D subjects. We report that children with new-onset T1D have an increased proportion of CD45RA(-)CD25(int)FOXP3(low) cells that are not suppressive and secrete significantly more IL-17 than other FOXP3(+) subsets. Moreover, these T1D subjects had a higher proportion of both CD4(+) and CD8(+) T cells that secrete IL-17. The bias toward IL-17-secreting T cells in T1D suggests a role for this proinflammatory cytokine in the pathogenesis of disease.

4: Journal of immunology (Baltimore, Md. : 1950), 2010 Aug 30, 30(11)
Inefficient Lymph Node Sensitization during Respiratory Viral Infection promotes IL-17-Mediated Lung Pathology.

[Abstract]Development of bronchus-associated lymphoid tissue has been suggested to enhance local antiviral immune responses; however, ectopic lymph node formation often corresponds to chronic inflammatory diseases. These studies investigated the role of ectopic pulmonary lymph nodes upon respiratory syncytial virus (RSV) infection using CCR7-deficient mice, which develop bronchus-associated lymphoid tissue early in life. CCR7(-/-) mice exhibited impaired secondary lymph node formation, enhanced effector T cell responses and pathogenic mucus production in the lung after RSV infection. IL-17 production from CD4 T cells in CCR7(-/-) mice was most remarkably enhanced. Wild-type animals reconstituted with CCR7(-/-) bone marrow recapitulated the pathogenic lung phenotype in CCR7(-/-) mice, whereas CCR7(-/-) animals reconstituted with wild-type bone marrow had normal lymph node development, diminished IL-17 production and reduced lung pathology. Mixed bone marrow chimeras revealed an alteration of immune responses only in CCR7(-/-) T cells, suggesting that impaired trafficking promotes local effector cell generation. Lymphotoxin-alpha-deficient mice infected with RSV were used to further examine locally induced immune responses and demonstrated increased mucus production and amplified cytokine responses in the lung, especially IL-17. Neutralization of IL-17 in CCR7(-/-) or in lymphotoxin-alpha-deficient animals specifically inhibited mucus hypersecretion and reduced IL-13. Thus, immune cell trafficking to secondary lymph nodes is necessary for appropriate cytokine responses to RSV as well as modulation of the local environment.

5: International immunopharmacology, 2010 Aug 23, 30(11)
Combined exercise training reduces IFN-gamma and IL-17 levels in the plasma and the supernatant of peripheral blood mononuclear cells in women with multiple sclerosis.

[Abstract]Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder in which lymphocytic infiltration mediated mainly by pro-inflammatory cytokines. In this study, we examined the effect of combined exercise training on the levels of IFN-gamma, IL-4 and IL-17 in the plasma and the supernatant of peripheral blood lymphocytes in women with multiple sclerosis. Expanded Disability Status Scale (EDSS), VO(2)max, muscle strength, and balance tests were obtained at baseline and post-treatment follow-up. Combined exercises training was designed for 24 sessions during 8weeks. Each session was started with 5min warm-up and was followed by 10min stretch training, 20min aerobic exercises and 20min resistance-endurance training. The disability score was significantly decreased in test MS subjects after 8weeks combined exercise training. Muscle strength and balance were increased significantly after the training program in test group. In this study, plasma, and peripheral blood mononuclear cell (PBMC) IL-17 and IFN-gamma production was significantly decreased after 8weeks combined training. Our findings suggest that combined training has useful anti-inflammatory effects by decrease in PBMC and plasma IL-17 production.

6: Oncogene, 2010 Aug 23, 47(15)
Up for Mischief? IL-17/Th17 in the tumour microenvironment.

[Abstract]The role of interleukin (IL)-17 and the IL-17-producing T helper (Th)17 cells in cancer has recently become the focus of extensive investigation. An expanding body of literature implicates Th17 cells and their hallmark cytokine in both pro- and anti-tumourigenic processes. In this review we describe their biological activities and outline the reciprocal interactions between Th17 cells and other cells of the immune system. We also discuss the evidence regarding their dual role in the tumour microenvironment. An understanding of the processes that regulate the pro- or anti-tumour activities of Th17 cell and IL-17 will allow the development of more effective means for cancer immunotherapy.Oncogene advance online publication, 23 August 2010; doi:10.1038/onc.2010.367.

7: Rheumatology (Oxford, England), 2010 Aug 19, 47(15)
Increased IL-17 production by peripheral T helper cells after tumour necrosis factor blockade in rheumatoid arthritis is accompanied by inhibition of migration-associated chemokine receptor expression.

[Abstract]Objectives. The contribution of IL-17-producing Th17 cells to the pathogenesis of T-cell-mediated inflammatory disorders such as RA and atopic dermatitis (AD) has to be viewed in relation to the role of Th1/Th2 cells and long-recognized key cytokines like TNF. We aimed to study the frequency and migration-associated phenotype of peripheral Th17, Th1 and Th2 cells in healthy individuals, RA and AD patients, and to study the influence of anti-TNF therapy in RA. Methods. Intracellular IL-17, IFN-gamma and IL-4 production and CC-chemokine receptor CCR4 and CCR6 expression were analysed flow cytometrically in peripheral memory Th cells from healthy individuals, AD and RA patients. The latter were grouped by disease activity and presence or absence of adalimumab therapy. In RA patients initiating anti-TNF therapy, cytokine production by in vitro-stimulated peripheral mononuclear cells was measured by cytometric bead array. Results. The peripheral Th17 cell frequency is elevated in AD but not in RA. In RA, Th17 cells and IL-17 production increase after anti-TNF therapy, irrespective of disease activity. Th1 cells and IFN-gamma production are elevated in remission and under anti-TNF therapy. CCR6 expression is up-regulated in Th17 cells, but RA patients in remission under anti-TNF therapy have significantly lower expression than those with active disease. Conclusions. The increase in peripheral Th17 cells in RA patients after anti-TNF therapy is accompanied by a decrease in Th17-specific CCR6 expression, which might prevent homing of these potentially pro-inflammatory cells to the synovium.

8: European cytokine network, 2010 Aug 19, 47(15)
IL-17 and HIV pathogenesis.

[Abstract]The role of interleukin (IL)-17 and the IL-17-producing T helper (Th)17 cells in cancer has recently become the focus of extensive investigation. An expanding body of literature implicates Th17 cells and their hallmark cytokine in both pro- and anti-tumourigenic processes. In this review we describe their biological activities and outline the reciprocal interactions between Th17 cells and other cells of the immune system. We also discuss the evidence regarding their dual role in the tumour microenvironment. An understanding of the processes that regulate the pro- or anti-tumour activities of Th17 cell and IL-17 will allow the development of more effective means for cancer immunotherapy.Oncogene advance online publication, 23 August 2010; doi:10.1038/onc.2010.367.

9: The British journal of dermatology, 2010 Aug 16, 47(15)
IL-22, IL-17, IL-23, VEGF, TNF-alpha and IL-8 levels in psoriatic patients - before, during and after PUVA and NBUVB therapy.

[Abstract]Abstract Background: Several cross-sectional studies showed that different cytokines and growth factors are enhanced in psoriasis. Objectives: We aimed to understand the role/relation of IL-22, IL-17, IL-23, VEGF, TNF-alpha and IL-8 in psoriasis vulgaris, addressing their changes before, during and after PUVA and NBUVB treatment. Methods: A cross-sectional and a longitudinal study (n=34) - before (T0), at 3 (T3), 6 (T6) and 12 (T12) weeks of NBUVB and PUVA therapy - were performed; 17 patients started NBUVB and 17 PUVA; IL-22, IL-17, IL-23, IL-8, TNF-alpha and VEGF levels were evaluated. Results: At T0, compared to control (n=20), all the parameters were significantly higher in patients, except for TNF-alpha. Both NBUVB and PUVA treatment showed, at T3, a significant decrease in TNF-alpha and IL-23; IL-22 and IL-17 decreased significantly at T6; at T12, all parameters and PASI decreased significantly. However, in both groups, at T12, VEGF was still significantly higher than control. Conclusions: Psoriasis seems to be a complex disease in which the cytokine network is disturbed, namely, in IL-22, IL-17, IL-23, IL-8, TNF-alpha and VEGF levels. NBUVB and PUVA follow-up studies suggested that the reduction in IL-23/Th17 axis might be important in the psoriasis pathogenic mechanisms. Further follow-up studies of psoriatic patients treated with these and other therapies could be very helpful for the understanding of the disturbance in cytokine network in psoriasis and indirectly in its pathogenesis.

10: The British journal of dermatology, 2010 Aug 12, 202(3)
Interleukin-17 expression in the urticarial rash of familial cold autoinflammatory syndrome: a case report.

[Abstract]Th17 cells are involved in host defense against several pathogens. Using interleukin (IL) 17RA-deficient mice, we demonstrated reduced ileitis with diminished neutrophil recruitment and inflammatory lesions in the ileum, in the regional lymph node, in the spleen, and in the liver at day 7 and prolonged survival after Toxoplasma gondii infection. In addition, IL-17A antibody neutralization reduced inflammation and enhanced survival in BL6 mice. Diminished inflammation is associated with augmented interferon (IFN) gamma serum levels and enhanced production of IL-10 and IFN-gamma in cultured splenocytes upon antigen restimulation. Finally, cyst load and inflammation in the brain at 40 days are greater in surviving BL6 mice than in IL-17RA-deficient mice. In conclusion, oral T. gondii infection increases IL-17 expression and contributes to the inflammatory response, and IL-17 neutralization has a partial protective effect against fatal T. gondii-associated inflammation.

11: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2010 Sep, 40(9)
Interleukin-17: a new role in steroid hypo-responsiveness?

[Abstract]Cite this as: P. Lavender, Clinical & Experimental Allergy, 2010 (40) 1293-1294.

12: The Journal of clinical investigation, 2010 Aug 9, 202(3)
Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice.

[Abstract]Deregulated production of IL-17 and IL-21 plays a key pathogenic role in many autoimmune disorders. A delineation of the mechanisms that underlie the inappropriate synthesis of IL-17 and IL-21 in autoimmune diseases can thus provide important insights into potential therapies for these disorders. Here we have shown that the serine-threonine kinase Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) becomes activated in mouse T cells under Th17 skewing conditions and phosphorylates interferon regulatory factor 4 (IRF4), a transcription factor that is absolutely required for the production of IL-17 and IL-21. We furthermore demonstrated that ROCK2-mediated phosphorylation of IRF4 regulated the synthesis of IL-17 and IL-21 and the differentiation of Th17 cells. Whereas CD4+ T cells from WT mice activated ROCK2 physiologically under Th17 conditions, CD4+ T cells from 2 different mouse models of spontaneous autoimmunity aberrantly activated ROCK2 under neutral conditions. Moreover, administration of ROCK inhibitors ameliorated the deregulated production of IL-17 and IL-21 and the inflammatory and autoantibody responses observed in these autoimmune mice. Our findings thus uncover a crucial link among ROCK2, IRF4, and the production of IL-17 and IL-21 and support the idea that selective inhibition of ROCK2 could represent an important therapeutic regimen for the treatment of autoimmune disorders.

13: Human reproduction (Oxford, England), 2010 Aug 4, 202(3)
The deregulation of regulatory T cells on interleukin-17-producing T helper cells in patients with unexplained early recurrent miscarriage.

[Abstract]BACKGROUND CD4(+)CD25(+) regulatory T cells (Tregs) are important for the maintenance of immune homeostasis by virtue of their ability to control T-cell proliferation in the peripheral blood (PB). We recently demonstrated that the prevalence of Tregs is decreased, whereas that of Th17 cells is increased, in the PB and decidua samples of patients with unexplained recurrent miscarriage (RM). In this study, we investigated whether the cytokine production of Th17 cells can be suppressed by the Tregs and elucidated the mechanism by which Tregs exert this suppressive effect. METHODS Flow cytometry was used to analyze the surface phenotype and cytokine production of Th17 cells in the PB of women with unexplained RM (n = 17) and healthy women in early stages of pregnancy who underwent elective abortion (n = 20). The suppressive ability of Tregs on Th17 cells was assessed in in vitro co-cultures and transwell experiments. The amount of secreted interleukin-17 (IL-17) in the supernatants was measured by enzyme-linked immunosorbent assay (ELISA). The inhibitory activity of transforming growth factor-beta (TGF-beta) and IL-10 on IL-17 expression in CD4(+) T cells was assessed using ELISA. RESULTS The proportions of IL-17-positive CD4(+) T cells, CC chemokine receptor type 6 (CCR6)-positive CD4(+) T cells and CCR6 expression of IL-17-positive CD4(+) T cells were higher in the PB samples of patients with unexplained RM than in PB of healthy control subjects. In vitro, Tregs could inhibit the expression of IL-17; more Th17 cells were inhibited in the control group than in the unexplained RM group. High-dose TGF-beta inhibited the expression of IL-17, whereas IL-10 inhibited IL-17 expression in a dose-dependent manner. CONCLUSIONS IL-17 expression can be inhibited by Tregs. The suppressive activity of Tregs on Th17 cells was decreased in patients with unexplained RM. The ability of Tregs to suppress cytokine secretion might be effected by a cell-cell contact. TGF-beta and IL-10 could inhibit the expression of IL-17.

14: Journal of neuroimmunology, 2010 Aug 2, 207(8)
Laquinimod interferes with migratory capacity of T cells and reduces IL-17 levels, inflammatory demyelination and acute axonal damage in mice with experimental autoimmune encephalomyelitis.

[Abstract]We investigated the effect of laquinimod on inflammatory demyelination, axonal damage, cytokine profiles and migratory capacities of lymphocytes in C57BL/6 mice with active EAE induced with MOG(35-55) peptide. The mice were treated at disease induction and after disease onset. Spinal cords were assessed histologically. Cytokines and adhesive properties were analyzed in splenocytes. Preventive and therapeutic laquinimod treatment reduced clinical signs, inflammation, and demyelination. VLA-4-mediated adhesiveness and pro-inflammatory cytokines such as IL-17 were down-regulated in treated animals. Within lesions, treated mice showed similar axonal densities, but less acute axonal damage than controls. Laquinimod might thus protect myelin and axons by decreasing pro-inflammatory cytokines and impairing the migratory capacity of lymphocytes.

15: Current opinion in lipidology, 2010 Jul 30, 104(8)
Interleukin-17: friend or foe in atherosclerosis?

[Abstract]PURPOSE OF REVIEW: To summarize the current knowledge on the origin and physiological function of T helper 17 (Th17) and discuss the contrasting results pertaining to the role of Th17 and interleukin-17 (IL-17) in atherosclerosis. RECENT FINDINGS: Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins. Although initial studies have focused on the role of Th1 and Th2 responses in atherosclerosis, more recent findings identified atheroprotective roles for several subsets of regulatory T cells. Th17 represents a new T-cell lineage with important roles in the clearance of pathogenic bacteria and fungi. The increase of Th17 and IL-17 has been recently linked to the pathogenesis of several autoimmune diseases. However, its role in chronic inflammatory diseases such as atherosclerosis remains poorly understood. The few studies available on this topic have generated contrasting results, which could be attributed to different approaches used on various mouse models. SUMMARY: IL-17 seems to have a modulatory role in atherosclerosis. Future studies are needed to better determine the molecular mechanisms involved in this regulation and examine whether targeting IL-17 pathway will be useful to treat cardiovascular diseases.

16: The Journal of rheumatology, 2010 Aug 3, 202(3)
The Relation of Interleukin 17 (IL-17) and IL-23 to Th1/Th2 Cytokines and Disease Activity in Systemic Lupus Erythematosus.

[Abstract]OBJECTIVE: Interleukin 17 (IL-17) was recently linked to pathogenesis of systemic lupus erythematosus (SLE), but its relation to disease activity has not been well characterized. We examined the relation between serum levels of Th17 (IL-17, IL-23), Th1 (IL-12, interferon-gamma), Th2 (IL-10, IL-6, IL-4) cytokines and disease activity in patients with SLE. METHODS: Serum cytokines were measured by enzyme linked immunosorbent assays. Disease activity was determined by SLE disease activity index (SLEDAI), anti-dsDNA antibody, and C3 and C4 levels. RESULTS: Serum levels of IL-17 (p < 0.001), IL-6 (p = 0.006) and IL-10 (p < 0.001) were higher in SLE patients (n = 70) compared to healthy controls (n = 36). Higher serum IL-23 level was found in patients with active disease with cutaneous manifestations (p = 0.004) and serositis (p = 0.04) compared to those without. Serum IL-17 level above the detection limit was more frequently found in patients who had active lupus nephritis (11/23, 47.8%) (p = 0.002), nonrenal active disease (9/15, 60%) (p = 0.001), and inactive lupus (21/32, 65.6%) (p < 0.001) compared to healthy controls (0%). Serum IL-17 levels were otherwise comparable between these 3 groups of patients and were not related to SLEDAI, glomerular filtration rate, activity or chronicity score and ISN/RPS criteria class among patients with active lupus nephritis. There was no significant correlation between serum IL-17/IL-23 and Th1 or Th2 cytokine levels. CONCLUSION: SLE patients had higher serum IL-17 levels than healthy controls. Elevated serum IL-23 was found in patients with inflammatory manifestations including cutaneous involvement and serositis. The lack of correlation between Th17, Th1, and Th2 cytokines suggested independent regulatory mechanisms for these cytokines.

17: Journal of leukocyte biology, 2010 Aug, 88(2)
Editorial: Be careful what you ask for: is the presence of IL-17 indicative of immunity?

[Abstract]The proinflammatory IL-17-producing CD8(+) T cells (Tc17 cells) have recently been detected in tumors, but the nature and regulation of these cells in human tumors are presently unknown. We have recently found that IL-17(+) cells are accumulated in human hepatocellular carcinomas (HCC), where they promote disease progression by fostering angiogenesis. In this study, we showed that Tc17 cells constitute a remarkable portion of IL-17-producing cells in human HCC. Although most circulating Tc17 cells were negative for IFN-gamma, >80% of Tc17 cells in HCC tissues were positive for IFN-gamma, and they were enriched predominantly in invading tumor edge. Most CD68(+) cells located in invading tumor edge exhibited an activated phenotype and, accordingly, the activated monocytes isolated from HCC tissues were significantly superior to those isolated from nontumor tissues in inducing expansion of Tc17 cells in vitro with phenotypic features similar to those isolated from tumors. Compared with IL-17(-)IFN-gamma(+)CD8(+) cells, these IFN-gamma(+)Tc17 cells have significantly higher expression of proinflammatory cytokines (IL-2, IL-22, and TNF-alpha), but reduced expression of granzyme B and perforin. Moreover, we found that tumor-activated monocytes secreted a set of key cytokines (IL-1beta, IL-6, and IL-23) to trigger the proliferation of Tc17 cells. These data reveal an intriguing mechanism in which human Tc17 cells are generated by a fine-tuned collaborative action between different types of immune cells in distinct tumor microenvironments.

18: Current opinion in immunology, 2010 Jul 29, 104(8)
Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines?

[Abstract]The various clinical manifestations of chronic mucocutaneous candidiasis (CMC) often result from acquired T-cell immunodeficiencies. More rarely, CMC results from inborn errors of immunity, the recent dissection of which has shed light on the molecular mechanisms of mucocutaneous immunity to Candida albicans. CMC may accompany various other infectious diseases in patients with almost any broad and profound T-cell primary immunodeficiency. By contrast, CMC is one of the few key infections in patients with autosomal dominant hyper IgE syndrome (mutations in STAT3), and in rare patients with autosomal recessive predisposition to mucocutaneous and invasive fungal infections (mutation in CARD9). In patients with mutations in STAT3 and CARD9, the development of IL-17-producing T cells is impaired. Moreover, CMC is the principal, if not only, infection in patients with autosomal recessive autoimmune polyendocrinopathy syndrome-I (mutations in AIRE). Patients with this condition have high titers of neutralizing autoantibodies (auto-Abs) against the IL-17 cytokines IL-17A, IL-17F, and IL-22. Collectively, these data suggest that human IL-17A, IL-17F, and IL-22 are essential for mucocutaneous immunity to C. albicans. They also suggest that the distinct syndrome of isolated CMC, without auto-immunity or other infections, may be caused by inborn errors of IL-17 immunity.

19: Metabolism: clinical and experimental, 2010 Jul 27, 7(1)
Decreased serum interleukin-17 and increased transforming growth factor-beta levels in subjects with metabolic syndrome (Chennai Urban Rural Epidemiology Study-95).

[Abstract]The term metabolic syndrome (MS) refers to a conglomeration of many metabolic disorders. Recent studies suggest that inflammation plays a vital role in MS. There are however no data available on the recently characterized novel T-cell-derived cytokine interleukin (IL)-17 in MS; studies on the anti-inflammatory cytokine transforming growth factor (TGF)-beta are also limited. The aim of the study was to look at IL-17 and TGF-beta levels in subjects with and without MS. The study subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES), a population-based study in Chennai (formerly Madras) in southern India. Group 1 consisted of subjects without MS (non-MS) (n = 98) and group 2 consisted of subjects with MS (n = 156). MS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria modified for waist, according to the World Health Organization Asia Pacific guidelines. Serum IL-17 and TGF-beta levels were estimated by enzyme-linked immunosorbent assay. Interleukin-17 levels were decreased (P < .001) and TGF-beta levels (P < .001) were increased in subjects with MS compared to those without. With an increase in the number of metabolic risk factors, the IL-17 levels showed a decline, whereas the TGF-beta levels showed an increase (P < .001). With respect to individual components of MS, TGF-beta and IL-17 showed a significant association with blood pressure and blood glucose even after adjusting for age and sex. We report that IL-17 levels are decreased, whereas TGF-beta levels are increased, among Asian Indians with MS.

20: Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2010 Jul 21, 12(4)
Interleukin-17 synergizes with IFNgamma or TNFalpha to promote inflammatory mediator release and intercellular adhesion molecule-1 (ICAM-1) expression in human intervertebral disc cells.

[Abstract]Interleukin-17 (IL-17) is a cytokine recently shown to be elevated, along with interferon-gamma (IFNgamma) and tumor necrosis factor (TNFalpha), in degenerated and herniated intervertebral disc (IVD) tissues, suggesting a role for these cytokines in intervertebral disc disease. The objective of our study was to investigate the involvement of IL-17 and costimulants IFNgamma and TNFalpha in intervertebral disc pathology. Cells were isolated from anulus fibrosus and nucleus pulposus tissues of patients undergoing surgery for intervertebral disc degeneration or scoliosis. The production of inflammatory mediators, nitric oxide (NOx), prostaglandin E2 (PGE2) and interleukin-6 (IL-6), as well as intercellular adhesion molecule (ICAM-1) expression, were quantified for cultured cells following exposure to IL-17, IFNgamma, and TNFalpha. Intervertebral disc cells exposed to IL-17, IFNgamma, or TNFalpha showed a remarkable increase in inflammatory mediator release and ICAM-1 expression (GLM and ANOVA, p < 0.05). Addition of IFNgamma or TNFalpha to IL-17 demonstrated a synergistic increase in inflammatory mediator release, and a marked increase in ICAM-1 expression. These findings suggest that IVD cells not only respond with a catabolic phenotype to IL-17 and costimulants IFNgamma and TNFalpha, but also express surface ligands with consequent potential to recruit additional lymphocytes and immune cells to the IVD microenvironment. IL-17 may be an important regulator of inflammation in the IVD pathologies. (c) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

21: Blood, 2010 Jul 27, 104(8)
A novel role of IL-17 producing lymphocytes in mediating lytic bone disease in multiple myeloma.

[Abstract]Osteoclast (OC) mediated lytic bone disease remains a cause of major morbidity in multiple myeloma (MM). Here we demonstrate the critical role of IL-17 producing marrow infiltrating lymphocytes (MILs) in OC activation and development of bone lesions in myeloma patients. Unlike MILs from normal bone marrow, myeloma MILs possess few regulatory T cells (Tregs) and demonstrate an IL-17 phenotype which enhances OC activation. In univariate analyses of factors mediating bone destruction, levels of cytokines that selectively induce and maintain the Th17 phenotype tightly correlated with the extent of bone disease in myeloma. In contrast, MILs activated under conditions that skew towards a Th1 phenotype significantly reduced formation of mature OC. These findings demonstrate that IL-17 T cells are critical to the genesis of myeloma bone disease, and that immunologic manipulations shifting MILs from a Th17 to a Th1 phenotype may profoundly diminish lytic bone lesions in MM.

22: Journal of inflammation (London, England), 2010 Jul 27, 7(1)
Increased expression of cardiac IL-17 after burn.

[Abstract]ABSTRACT: BACKGROUND: Cardiac dysfunction is a common complication associated with major burns. While recent findings have linked the Th-17 T-cell response to the development of autoimmune myocarditis, the role of IL-17 and the Th-17 T-cell response in the development of post-burn cardiac dysfunction remains unknown. METHODS: Male C57BL/6 mice were subjected to a major burn (3rd degree, 25 percent TBSA) or sham treatment. Three hours after injury plasma and tissue (i.e., heart, lung, liver, small intestine) samples were collected and analyzed for the expression of Th-17 cytokine (i.e., IL-6, IL-17, IL-22, IL-23, TGF-beta) levels by ELISA. RESULTS: Cardiac tissue levels of the Th-17 cytokines, IL-6, IL-17 and IL-22 were significantly elevated at 3 hrs after burn as compared to sham levels. IL-17 was analyzed 1, 3 and 7 days after burn and showed a return to baseline levels and without a difference in the burn group. Burn-induced alterations in the level of these cytokines in plasma or other tissues were not evident. The cardiac Th-17 cytokine response after burn injury was specific, as cardiac levels of Th-1 (IFN-gamma) and Th-2 (IL-10) cytokines were not significantly affected after injury. The cardiac Th-17 response correlated with a significant increase in Troponin levels at 3 hr. after burn. CONCLUSION: These findings indicate that early after burn, cardiac tissue is associated with significantly elevated levels of Th-17 cytokines. The early Th-17 response after burn appears to be specific for cardiac tissue and may promote myocardial inflammation and dysfunction associated with this form of trauma.

23: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2010 Jul 27, 104(8)
Mechanism of Neuroinflammation: Enhanced Cytotoxicity and IL-17 Production via CD46 Binding.

[Abstract]The membrane co-factor protein CD46 is the cellular receptor for a number of pathogens including the human herpesvirus 6 (HHV-6). In addition to its function as an inhibitory complement receptor, engagement of CD46 in the context of T-cell receptor (TCR) signaling influences T-cell activation. Simultaneous cross-linking of the CD3/CD46 molecules led to differentiation of a unique population of CD4+ T-cell subset characterized by enhanced expressions of IFN-gamma, IL-10, granzyme B, adhesion molecule MAdCAM-1 (alpha-4-beta-7), surface-bound cytokine LIGHT, and chemokine receptor CCR9. Multiple sclerosis is a chronic inflammatory neurodegenerative disorder of the central nervous system (CNS) with unknown etiology. The HHV-6 is a candidate pathogen in MS and uses the CD46 molecule as its receptor. We hypothesize that binding of the HHV-6 glycoprotein to CD46 may trigger a pro-inflammatory response that could contribute to CNS tissue damage. To address this question, we examined immunological parameters such as proliferation, cytokine production and cytotoxic functions in CD4+ T cells of healthy individuals and MS patients following CD3/CD46 co-engagement by using anti-CD3 and anti-CD46 monoclonal antibodies as surrogates to mimic T-cell receptor and CD46 signaling. Our results demonstrated that CD3/CD46 cross-linking induced expression of IL-1beta and IL-17A in multiple sclerosis patient T cells. Additionally, increase in transient surface expression of lysosomal associated protein CD107a suggested enhanced CD4+ T-cell cytotoxic functions following CD3/CD46 co-stimulation. Collectively, this study demonstrated evidence to suggest a potential mechanism of virus-induced neuroinflammation that may be involved in MS disease pathogenesis.

24: Journal of immunology (Baltimore, Md. : 1950), 2010 Aug 1, 185(3)
Comment on "CCR5 Dictates the Equilibrium of Proinflammatory IL-17+ and Regulatory Foxp3+ T Cells in Fungal Infections".

[Abstract]Reports describing the effect of interferon-gamma (IFNgamma) on interleukin-1beta (IL-1beta) production are conflicting. We resolve this controversy by showing that IFNgamma potentiates IL-1beta release from human cells, but transiently inhibits the production of IL-1beta from mouse cells. Release from this inhibition is dependent on suppressor of cytokine signalling 1. IL-1beta and Th17 cells are pathogenic in mouse models for autoimmune disease, which use Mycobacterium tuberculosis (MTB), in which IFNgamma and IFNbeta are anti-inflammatory. We observed that these cytokines suppress IL-1beta production in response to MTB, resulting in a reduced number of IL-17-producing cells. In human cells, IFNgamma increased IL-1beta production, and this might explain why IFNgamma is detrimental for multiple sclerosis. In mice, IFNgamma decreased IL-1beta and subsequently IL-17, indicating that the adaptive immune response can provide a systemic, but transient, signal to limit inflammation.

25: Arthritis research & therapy, 2010 Jul 23, 12(4)
Increased expression of costimulatory markers CD134 and CD80 on interleukin-17 producing T cells in patients with systemic lupus erythematosus.

[Abstract]ABSTRACT: INTRODUCTION: There is growing evidence that interleukin 17 (IL-17) producing T cells are involved in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies showed that increased percentages of T-cell subsets expressing the costimulatory molecules CD80 and CD134 are associated with disease activity and renal involvement in SLE. The aim of this study was to investigate the distribution and phenotypical characteristics of IL 17 producing T-cells in SLE, in particular in patients with lupus nephritis, with emphasis on the expression of CD80 and CD134. METHODS: Thirty-four patients (3 male, 31 female, mean age 41 +/-15 years) fulfilling at least four of the American College of Rheumatology (ACR) revised criteria for the diagnosis of SLE and 24 healthy controls were enrolled. T-cells from the peripheral blood were analysed by fluorescence activated cell sorting (FACS) for their expression levels of CD80, CD134 and CCR6. In vitro stimulated CD3+IL17+ cells were also investigated for the expression of these costimulatory markers. Finally, renal biopsies from SLE patients were evaluated for the presence of CD134 expressing T-cells. RESULTS: Percentages of IL-17 expressing T-cells were significantly increased in patients with active disease as compared to healthy controls (1.46 +/-0.58% versus 0.93 +/-0.30%, P=0.007). The percentage of IL-17 producing T-cells was correlated with disease activity as assessed by systemic lupus erythematosus disease activity index (SLEDAI) (r=0.53, P=0.003). In patients, most of the IL-17 producing T-cells were confined to the CCR6+ T-cell subset (80 +/-13%). Expression of CD80 and CD134 on the IL-17 producing T-cell subset was higher in SLE than in healthy controls (HC) (CD134: 71.78 +/-14.51% versus 51.45 +/-16.58%, P=0.002; CD80: 25.5 +/-14.99% versus 14.99 +/-5.74%, P=0.02). Also, patients with lupus nephritis expressed higher levels of CD134+ on CD3+IL-17+ cells as compared to HC (72.69 +/-11.54% versus 51.45 +/-16.58%, P=0.006). Furthermore, renal biopsies of lupus nephritis patients showed infiltration of CD134+ T cells. CONCLUSIONS: Percentages IL-17 expressing T-cells correlate with disease activity. Further, these cells show increased expression of costimulatory markers such as CD134 and CD80. The presence of CD134+ T-cells in renal biopsies of lupus nephritis patients suggest that these cells migrate to the kidney and might contribute to inflammatory processes through IL-17 secretion.

26: The American journal of pathology, 2010 Jul 22, 104(8)
Interleukin-17 Promotes Early Allograft Inflammation.

[Abstract]Acute cellular rejection of organ transplants is executed by donor-reactive T cells, which are dominated by interferon-gamma-producing cells. As interferon-gamma is dispensable for graft destruction, we evaluated the contribution of interleukin-17A (IL-17) to intragraft inflammation in major histocompatibility complex-mismatched heart transplants. A/J (H-2(a)) cardiac allografts placed into wild-type BALB/c (H-2(d)) mice induced intragraft IL-17 production on day 2 after transplant. Allografts placed into BALB/c IL-17(-/-) recipients demonstrated diminished production of the chemokines CXCL1 and CXCL2 and delayed neutrophil and T cell recruitment. However, by day 7 after transplant, allografts from IL-17(-/-) and wild-type recipients had comparable levels of cellular infiltration. The priming of donor-specific T cells was not affected by the absence of IL-17, and the kinetics of cardiac allograft rejection were similar in wild-type and IL-17(-/-) recipients. In contrast, IL-17(-/-) mice depleted of CD8 T cells rejected A/J allografts in a delayed fashion compared with CD8-depleted wild-type recipients. Although donor-reactive CD4 T cells were efficiently activated in both groups, the infiltration of effector T cells into allografts was impaired in IL-17(-/-) recipients. Our data indicate that locally produced IL-17 amplifies intragraft inflammation early after transplantation and promotes tissue injury by facilitating T cell recruitment into the graft. Targeting the IL-17 signaling network in conjunction with other graft-prolonging therapies may decrease this injury and improve the survival of transplanted organs.

27: Autoimmunity reviews, 2010 Jul 17, 104(8)
Interleukin-17-producing T helper cells in autoimmunity.

[Abstract]With all the incredible progress in scientific research over the past two decades, the trigger of the majority of autoimmune disorders remains largely elusive. Research on the biology of T helper type 17 (T(H)17) cells over the last decade not only clarified previous observations of immune regulations and disease manifestations, but also provided considerable information on the signaling pathways mediating the effects of this lineage and its seemingly dual role in fighting the invading pathogens on one hand, and in frightening the host by inducing chronic inflammation and autoimmunity on the other hand. In this context, recent reports have implicated T(H)17 cells in mediating host defense as well as a growing list of autoimmune diseases in genetically-susceptible individuals. Herein, we summarize the current knowledge on T(H)17 in autoimmunity with emphasis on its differentiation factors and some mechanisms involved in initiating pathological events of autoimmunity.

28: Journal of immunology (Baltimore, Md. : 1950), 2010 Jul 19, 104(8)
Delaying Bacillus Calmette-Guerin Vaccination from Birth to 4 1/2 Months of Age Reduces Postvaccination Th1 and IL-17 Responses but Leads to Comparable Mycobacterial Responses at 9 Months of Age.

[Abstract]Bacillus Camette-Gu��rin (BCG) vaccine is the only licensed vaccine against tuberculosis, yet its protective efficacy is highly variable between different geographical regions. We hypothesized that exposure to nontuberculous mycobacteria attenuates BCG immunogenicity by inducing mycobacterial-specific regulatory T cells (Tregs). Gambian neonates were recruited at birth and randomized to receive BCG vaccination either at birth or at 4 1/2 mo. Mycobacterial immune responses were assessed at birth, 4 1/2, and 9 mo of age. At 4 1/2 mo of age the BCG naive individuals had detectable mycobacterial responses, including increased IL-10 production suggesting environmental priming. Vaccination at birth significantly enhanced Th1, Th2, IL-6, IL-17, and Treg responses in mycobacterial cultures at 4 1/2 mo compared with the BCG naive group. Analyzing results at 4 1/2 mo postvaccination revealed lower IFN-gamma, IL-6, and IL-17 responses in the delayed BCG vaccine group compared with those vaccinated at birth, but this did not relate to Treg levels prevaccination. When comparing responses pre- and post-BCG vaccination in the delayed vaccine group, there was no priming of mycobacterial IL-17. Mycobacterial responses waned over 9 mo in those vaccinated at birth, leading to comparable mycobacterial immunity in both groups at 9 mo of age. Overall, these data suggest that vaccination at birth induces a broad Th1/Th2/IL-17/Treg mycobacterial response but the Th1/Th-17 response was reduced when delaying the vaccine. The evidence did not suggest that mycobacterial specific naturally occurring Tregs accounted for this attenuated immunogenicity.

29: Journal of immunology (Baltimore, Md. : 1950), 2010 Jul 14, 185(2)
TLR4 Activation Is Required for IL-17-Induced Multiple Tissue Inflammation and Wasting in Mice.

[Abstract]IL-17 is a recently identified proinflammatory cytokine that plays pivotal roles in several chronic inflammatory disease models. Its expression was also found to be elevated in the serum of patients with chronic diseases. However, whether elevated systemic IL-17 expression can induce pathophysiological tissue inflammation is unknown. In this study, we demonstrated that systemic overexpression of IL-17 using an adenoviral vector could induce multiple tissue inflammation and wasting in mice. We also found that the expression of TLR4 was increased in tissues of IL-17-overexpressing mice. Moreover, TLR4 activation is required for IL-17-induced tissue inflammation and wasting, as evidenced by the absence of aggressive atrophy in gastrocnemius muscle, neutrophil accumulation, and expression of proinflammatory cytokines downstream of TLR4 in multiple tissues of TLR4-deficient mice. Further investigation revealed that TLR4 endogenous ligands high-mobility group box 1 and heat shock protein 22, were systemically upregulated and might be involved in the IL-17-induced TLR4 activation. Our results suggest that IL-17 may induce disease-associated tissue inflammation and wasting through TLR4 signaling. The study indicates a novel interaction between IL-17 and TLR4 activation and may have implications in the pathogenesis and treatment of chronic diseases.

30: Journal of immunology (Baltimore, Md. : 1950), 2010 Jul 12, 185(2)
Respiratory Virus-Induced TLR7 Activation Controls IL-17-Associated Increased Mucus via IL-23 Regulation.

[Abstract]The response to respiratory syncytial virus (RSV), negative strand ssRNA virus, depends upon the ability to recognize specific pathogen-associated targets. In the current study, the role of TLR7 that recognizes ssRNA was examined. Using TLR7(-/-) mice, we found that the response to RSV infection in the lung was more pathogenic as assessed by significant increases in inflammation and mucus production. Although there appeared to be no effect of TLR7 deficiency on type I IFN, the pathology was associated with an alteration in T cell responses with increases in mucogenic cytokines IL-4, IL-13, and IL-17. Examination of dendritic cells from TLR7(-/-) animals indicated a preferential activation of IL-23 (a Th17-promoting cytokine) and a decrease in IL-12 production. Neutralization of IL-17 in the TLR7(-/-) mice resulted in a significant decrease in the mucogenic response in the lungs of the RSV-infected mice. Thus, without TLR7-mediated responses, an altered immune environment ensued with a significant effect on airway epithelial cell remodeling and goblet cell hyper/metaplasia, leading to increased mucus production.

31: Journal of immunology (Baltimore, Md. : 1950), 2010 Jul 12, 185(2)
Candida albicans Dampens Host Defense by Downregulating IL-17 Production.

[Abstract]IL-17 is one of the key cytokines that stimulate host defense during a Candida infection. Several studies have demonstrated the capacity of Candida albicans to induce a Th17 response. Surprisingly, experiments employing live C. ablicans demonstrated a specific downregulation of host IL-17 secretion in human blood mononuclear cells (PBMCs). By avoiding the direct contact of live C. albicans and PBMCs, we demonstrate that this inhibition effect is mediated by a soluble factor released by live C. albicans. However, this effect is due neither to the releasing of C. albicans pathogen-associated molecular patterns nor to the alteration of different Th cell subtypes. Rather, we found that live C. albicans shifts tryptophan metabolism by inhibiting IDO expression away from kynurenines and toward 5-hydroxytryptophan metabolites. In addition, we show that these latter 5-hydroxytryptophan metabolites inhibit IL-17 production. In conclusion, live C. albicans inhibits host Th17 responses by modulatory effects on tryptophan metabolism.

32: The Journal of experimental medicine, 2010 Jul 12, 185(2)
Pathological role of interleukin 17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis.

[Abstract]Infection usually leads to the development of acquired immune responses associated with clearance or control of the infecting organism. However, if not adequately regulated, immune-mediated pathology can result. Tuberculosis is a worldwide threat, and development of an effective vaccine requires that the protective immune response to Mycobacterium tuberculosis (Mtb) be dissected from the pathological immune response. This distinction is particularly important if new vaccines are to be delivered to Mtb-exposed individuals, as repeated antigenic exposure can lead to pathological complications. Using a model wherein mice are vaccinated with bacille Calmette-Gu��rin after Mtb infection, we show that repeated vaccination results in increased IL-17, tumor necrosis factor, IL-6, and MIP-2 expression, influx of granulocytes/neutrophils, and lung tissue damage. This pathological response is abrogated in mice deficient in the gene encoding IL-23p19 or in the presence of IL-17-blocking antibody. This finding that repeated exposure to mycobacterial antigen promotes enhanced IL-17-dependent pathological consequences has important implications for the design of effective vaccines against Mtb.

33: European journal of immunology, 2010 Jul 7, 185(2)
Estrogen increases, whereas IL-27 and IFN-gamma decrease, splenocyte IL-17 production in wild type mice.

[Abstract]Estrogen-mediated regulation of Th1, Th2 and Treg effector functions are well documented but, surprisingly, it is still not known whether estrogen modulates IL-17, a powerful proinflammatory cytokine that plays a pivotal role in several inflammatory and autoimmune diseases. Therefore in the present study, we determined whether estrogen regulates the expression levels of IL-17 in wildtype C57BL/6 mice. By ELISA, ELISPOT and/or flow cytometric analyses, we found that estrogen upregulated the levels of not only IL-17, but also the IL-17-specific transcription factor retinoic acid-related orphan receptor gamma t (RORgammat), in activated splenocytes. IL-17 levels were further enhanced by exposure of activated splenocytes to IL-23, particularly in cells from estrogen-treated mice. Exposure of splenocytes to IL-27 or IFN-gamma at the time of activation markedly inhibited the levels of IL-17 and RORgammat. Interestingly, a delay of 24 hours in exposure of activated splenocytes to IL-27 or IFN-gamma decreased IL-17 levels (albeit less profoundly) but not RORgammat. These findings imply that the suppressive effects of IL-27 and IFN-gamma are more effective prior to the differentiation and commitment of IL-17-secreting cells. Furthermore, inhibition of JAK-2 by AG490 suppressed IL-17 but not RORgammat expression suggesting that other transcription factors are also critical in estrogen-mediated upregulation of IL-17.

34: Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 2010 Jul 1, 51(7)
Infliximab Reduces the Frequency of Interleukin 17-Producing Cells and the Amounts of Interleukin 17 in Patients With Rheumatoid Arthritis.

[Abstract]BACKGROUND:: To detect frequency changes in interleukin 17 (IL-17) CD4 T cells and the amounts of IL-17 in supernatants between baseline and 30 weeks after Infliximab combined with methotrexate (MTX) or MTX-alone therapy. METHODS:: Flow cytometry was used to analyze the frequency of IL-17 CD4 T cells in rheumatoid arthritis (RA) patients and control subjects at baseline and 30 weeks after therapy. Secretion of IL-17 by peripheral blood mononuclear cells was measured by enzyme-linked immunosorbent assay. RESULTS:: The percentages of IL-17 CD4T cells were increased in the peripheral blood mononuclear cells of patients with RA compared with healthy subjects. The percentages of IL-17 CD4T cells were correlated with the number of swelling joints and C-reactive protein of RA patients. Likewise, concentrations of IL-17 in supernatants from patients with RA were significantly higher compared with those from control subjects. After infliximab combined with MTX or MTX-alone therapy, the number of swelling joints, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and Disease Activity Score 28 decreased significantly compared with baseline. Only in the infliximab + MTX group that the frequency of TH17 cells and concentration of IL-17 decreased. CONCLUSIONS:: These data support the hypothesis that infliximab therapy can have an effect on TH17 cells and decrease disease activity.

35: Contact dermatitis, 2010 Jul, 63(1)
Nickel (Ni) allergic patients with complications to Ni containing joint replacement show preferential IL-17 type reactivity to Ni.

[Abstract]BACKGROUND: Some nickel (Ni) allergic patients develop complications following Ni-containing arthroplasty. In the peri-implant tissue of such patients, we had observed lymphocyte dominated inflammation together with IFN-gamma and IL-17 expression. OBJECTIVES: To determine whether Ni stimulation of peripheral blood mononuclear cells (PBMCs) of such patients would lead to a different cytokine pattern as compared to Ni-allergic patients with symptom-free arthroplasty. PATIENTS AND METHODS: Based on history and patch testing in 15 Ni-allergic patients (five without implant, five with symptom-free arthroplasty, five with complicated arthroplasty) and five non-allergic individuals, lymphocyte transformation test (LTT) was performed using PBMC. In parallel in vitro cytokine response to Ni was assessed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: All 15 Ni-allergic individuals showed enhanced LTT reactivity to Ni (mean SI = 8.42 +/- 1.8) compared to the non-allergic control group. Predominant IFN-gamma expression to Ni was found both in the five allergic patients without arthroplasty and also in the five allergic, symptom-free arthroplasty patients. In contrast, in the five Ni-allergic patients with arthroplasty-linked complications a predominant, significant IL-17 expression to Ni was seen but not in patients with symptom-free arthroplasty. CONCLUSIONS: The predominant IL-17 type response to Ni may characterize a subgroup of Ni-allergic patients prone to develop lymphocytic peri-implant hyper-reactivity.

36: Tuberculosis (Edinburgh, Scotland), 2010 Jun 29, 126(1)
Regulatory T cell frequency and modulation of IFN-gamma and IL-17 in active and latent tuberculosis.

[Abstract]Regulatory T cells (Tregs) play an essential role in immune homeostasis. In infectious diseases Tregs may inhibit protective responses facilitating pathogen multiplication and dissemination, but they may also limit the inflammatory response diminishing tissue damage. Although there is experimental and clinical evidence that Tregs are induced during Mycobacterium tuberculosis infection, their role in the immunopathogenesis of tuberculosis is still not completely understood. In this study, the phenotype, frequency and activity of circulating Tregs in active and latent tuberculosis were evaluated. Phenotypic analysis showed that Tregs were CD4(+)CD25(high)FOXP3(+)CD45RO(+)CD127(-). High levels of circulating Tregs were found in patients with active pulmonary tuberculosis, compared to individuals with latent infection. Treg activity was evaluated by ELISPOT by determining the effect of CD25(+) cell depletion on the frequency of IFN-gamma and IL-17 producing cells after in vitro stimulation with ESAT-6, CFP-10 and PPD. Treg depletion increased the frequency of IFN-gamma producing cells, without affecting the frequency of IL-17 producing cells, in both active and latent tuberculosis, irrespective of the antigen used. Neutralization of IL-10 did not have any effect on the frequency of IFN-gamma and IL-17 producing cells. Altogether, these results suggest that during active tuberculosis Tregs inhibit protective Th1 responses, but not the proinflammatory Th17 responses, facilitating mycobacterial replication and tissue damage.

37: Current opinion in rheumatology, 2010 Jun 28, 25(7)
Interleukin-17-producing T cells in lupus.

[Abstract]PURPOSE OF REVIEW: Interleukin-17 (IL-17) has emerged as a key cytokine involved in the pathogenesis of autoimmune diseases. In this article, we review recently produced evidence obtained in patients and murine models of lupus that link increased IL-17 production with lupus pathology and discuss the potential roles IL-17 may play in the pathogenesis of systemic lupus erythematosus. RECENT FINDINGS: IL-17 may promote autoantibody production and IL-17-producing cells are found in afflicted organs in humans and lupus-prone mice. TH17 and CD3CD4CD8 cells are expanded in systemic lupus erythematosus patients and account for the increased production of IL-17. Genetic silencing of genes involved in the increased production of IL-17 in lupus-prone mice as well as treatment of mice with lupus using biologic agents that result in decreased IL-17 production leads invariably to disease mitigation. SUMMARY: The presented evidence strongly argues for the introduction of IL-17-suppressing biologics in the treatment of patients with systemic lupus erythematosus.

38: Journal of immunology (Baltimore, Md. : 1950), 2010 Jun 30, 25(7)
IL-17 Immunity in Human Type 1 Diabetes.

[Abstract]Th17 immunity has been shown to regulate autoimmune diabetes in mice. IL-17 neutralization prevented development of diabetes when given postinitiation of insulitis but not earlier, suggesting interference with the effector phase of the disease. Islet-cell Ag-specific Th17 cells converted into IFN-gamma-secreting Th1-like cells and caused diabetes in mice recipients. The role of IL-17 in human type 1 diabetes (T1D) is, however, not established. In this study, we show upregulation of Th17 immunity in peripheral blood T cells from children with T1D. This was characterized by increased IL-17 secretion and expression of IL-17, IL-22, and retinoic acid-related orphan receptor C isoform 2, but also FOXP3 transcripts upon T cell activation in vitro. Also, circulating memory CD4 cells from children with T1D showed the same pattern of IL-17, IL-22 and FOXP3 mRNA upregulation, indicating IL-17 pathway activation in vivo. IL-17-positive T cells appeared to be CD4(+) cells expressing TCR-alphabeta and CCR6, and a subpopulation showed coproduction of IFN-gamma. Given the Th17 immunity in T1D, we demonstrated that IL-17 had detrimental effects on human islet cells in vitro; it potentiated both inflammatory and proapoptotic responses. Our findings highlight the role of IL-17 immunity in the pathogenesis of human T1D and point to a potential therapeutic strategy.

39: Journal of immunology (Baltimore, Md. : 1950), 2010 Jun 25, 25(7)
Tumor-Activated Monocytes Promote Expansion of IL-17-Producing CD8+ T Cells in Hepatocellular Carcinoma Patients.

[Abstract]The proinflammatory IL-17-producing CD8(+) T cells (Tc17 cells) have recently been detected in tumors, but the nature and regulation of these cells in human tumors are presently unknown. We have recently found that IL-17(+) cells are accumulated in human hepatocellular carcinomas (HCC), where they promote disease progression by fostering angiogenesis. In this study, we showed that Tc17 cells constitute a remarkable portion of IL-17-producing cells in human HCC. Although most circulating Tc17 cells were negative for IFN-gamma, >80% of Tc17 cells in HCC tissues were positive for IFN-gamma, and they were enriched predominantly in invading tumor edge. Most CD68(+) cells located in invading tumor edge exhibited an activated phenotype and, accordingly, the activated monocytes isolated from HCC tissues were significantly superior to those isolated from nontumor tissues in inducing expansion of Tc17 cells in vitro with phenotypic features similar to those isolated from tumors. Compared with IL-17(-)IFN-gamma(+)CD8(+) cells, these IFN-gamma(+)Tc17 cells have significantly higher expression of proinflammatory cytokines (IL-2, IL-22, and TNF-alpha), but reduced expression of granzyme B and perforin. Moreover, we found that tumor-activated monocytes secreted a set of key cytokines (IL-1beta, IL-6, and IL-23) to trigger the proliferation of Tc17 cells. These data reveal an intriguing mechanism in which human Tc17 cells are generated by a fine-tuned collaborative action between different types of immune cells in distinct tumor microenvironments.

40: Journal of clinical immunology, 2010 Jun 23, 3(4)
IL-2 Immunotherapy to Recently HIV-1 Infected Adults Maintains the Numbers of IL-17 Expressing CD4+ T (T(H)17) Cells in the Periphery.

[Abstract]Little is known about the manipulation of IL-17 producing CD4+ T cells (T(H)17) on a per-cell basis in humans in vivo. Previous studies on the effects of IL-2 on IL-17 secretion in non-HIV models have shown divergent results. We hypothesized that IL-2 would mediate changes in IL-17 levels among recently HIV-1-infected adults receiving anti-retroviral therapy. We measured cytokine T cell responses to CD3/CD28, HIV-1 Gag, and CMV pp65 stimulation, and changes in multiple CD4+ T cell subsets. Those who received IL-2 showed a robust expansion of naive and total CD4+ T cell counts and T-reg counts. However, after IL-2 treatment, the frequency of T(H)17 cells declined, while counts of T(H)17 cells did not change due to an expansion of the CD4+ na?ve T cell population (CD27+CD45RA+). Counts of HIV-1 Gag-specific T cells declined modestly, but CMV pp65 and CD3/CD28 stimulated populations did not change. Hence, in contrast with recent studies, our results suggest IL-2 is not a potent in vivo regulator of T(H)17 cell populations in HIV-1 disease. However, IL-2-mediated T-reg expansions may selectively reduce responses to certain antigen-specific populations, such as HIV-1 Gag.

41: Mucosal immunology, 2010 Jun 23, 3(4)
HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22.

[Abstract]We have analyzed the production of the effector cytokines interleukin (IL)-17, IL-21, and IL-22 in gluten-reactive CD4(+) T cells of celiac disease patients, either cultured from small intestinal biopsies or isolated from peripheral blood after an oral gluten challenge. Combining intracellular cytokine staining with DQ2-alpha-II gliadin peptide tetramer staining of intestinal polyclonal T-cell lines, we found that gluten-specific T cells produced interferon-gamma (IFN-gamma) and IL-21, but not IL-17 or IL-22, even if other T cells of the same lines produced these cytokines. Similarly, in DQ2-alpha-II-specific T cells in peripheral blood of gluten-challenged patients, very few stained for intracellular IL-17, whereas many cells stained for IFN-gamma. We conclude that gluten-reactive T cells produce IL-21 and IFN-gamma, but not IL-17. Their production of IL-21 suggests a role for this cytokine in the pathogenesis of celiac disease.Mucosal Immunology advance online publication 23 June 2010. doi:10.1038/mi.2010.36.

42: Journal of immunology (Baltimore, Md. : 1950), 2010 Jun 21, 107(25)
TLR5 Signaling Stimulates the Innate Production of IL-17 and IL-22 by CD3negCD127+ Immune Cells in Spleen and Mucosa.

[Abstract]In adaptive immunity, Th17 lymphocytes produce the IL-17 and IL-22 cytokines that stimulate mucosal antimicrobial defenses and tissue repair. In this study, we observed that the TLR5 agonist flagellin induced swift and transient transcription of genes encoding IL-17 and IL-22 in lymphoid, gut, and lung tissues. This innate response also temporarily enhanced the expression of genes associated with the antimicrobial Th17 signature. The source of the Th17-related cytokines was identified as novel populations of CD3(neg)CD127(+) immune cells among which CD4-expressing cells resembling lymphoid tissue inducer cells. We also demonstrated that dendritic cells are essential for expression of Th17-related cytokines and so for stimulation of innate cells. These data define that TLR-induced activation of CD3(neg)CD127(+) cells and production of Th17-related cytokines may be crucial for the early defenses against pathogen invasion of host tissues.

43: Respiratory research, 2010 Jun 16, 11(1)
Interleukin-17 regulation: an attractive therapeutic approach for asthma.

[Abstract]ABSTRACT: Interleukin (IL)-17 is recognized to play a critical role in numerous immune and inflammatory responses by regulating the expression of various inflammatory mediators, which include cytokines, chemokines, and adhesion molecules. There is growing evidence that IL-17 is involved in the pathogenesis of asthma. IL-17 orchestrates the neutrophilic influx into the airways and also enhances T-helper 2 (Th2) cell-mediated eosinophilic airway inflammation in asthma. Recent studies have demonstrated that not only inhibitor of IL-17 per se but also diverse regulators of IL-17 expression reduce antigen-induced airway inflammation, bronchial hyperresponsiveness, and Th2 cytokine levels in animal models of asthma. This review will summarize the role of IL-17 in the context of allergic airway inflammation and discuss the therapeutic potential of various strategies targeting IL-17 for asthma.

44: Clinical rheumatology, 2010 Jun 19, 107(25)
The imbalance between regulatory and IL-17-secreting CD4(+) T cells in lupus patients.

[Abstract]It has been well recognized that a deficit of numbers and function of CD4(+)CD25(+)Foxp3(+) cells (Treg) is attributed to the development of some autoimmune diseases; however, there are controversial data regarding the suppressive effect of Treg cells on the T cell response in systemic lupus erythematosus (SLE). Additionally, IL-17-producing cells (Th17) have been recently emerged as a new pathogenic cell, but their role in lupus remains unclear. In this study, we studied the connection between Treg and Th17 cells in lupus patients. We observed that, while Treg or Th17 cells alone were not correlated to SLE development, the ratio of Treg to Th17 cells in active SLE patients is significantly lower than that in inactive SLE patients and healthy controls, and we also found corticosteroid treatment increased the ratio of Treg to Th17 cells in active SLE patients. Moreover, this ratio is inversely correlated with the severity of active SLE. The present study indicates that active SLE appears to exist as an imbalance between Treg and Th17 cells. Correction of this Treg/Th17 imbalance may have therapeutic impact for patients with SLE.

45: Journal of immunology (Baltimore, Md. : 1950), 2010 Jun 18, 107(25)
IL-17 Is Necessary for Host Protection against Acute-Phase Trypanosoma cruzi Infection.

[Abstract]IL-17A is a key cytokine that induces inflammatory responses through the organized production of inflammatory cytokines, such as IL-6, TNF-alpha, and GM-CSF, and induces neutrophil migration. The roles of IL-17A in infection of intracellular protozoan parasites have not been elucidated, although augmented immune responses by IL-17A are important for the resolution of some bacterial and fungal infections. Therefore, we experimentally infected IL-17A-deficient (IL-17A(-/-)) mice with Trypanosoma cruzi. IL-17A(-/-) mice had a lower survival rate and prolonged worse parasitemia compared with control C57BL/6 wild-type (WT) mice postinfection. In the infected IL-17A(-/-) mice, multiple organ failure was observed compared with WT mice, as reflected by the marked increase in serologic markers of tissue injury, such as aspartate aminotransferase, which resulted in increased mortality of IL-17A(-/-) mice. Expression of cytokines, such as IFN-gamma, IL-6, and TNF-alpha, was lower in liver-infiltrating cells from the IL-17A(-/-) mice compared with WT mice. A similar defect was observed in the expression of neutrophil enzymes, such as myeloperoxidase and lipoxygenase, whereas cellular infiltration into the infected tissues was not affected by IL-17A deficiency. These results suggested that the efficient activation of immune-related cells critical for the killing of T. cruzi was impaired in the absence of IL-17A, resulting in the greater susceptibility of those mice to T. cruzi infection. From these results, we conclude that IL-17A is important for the resolution of T. cruzi infection.

46: Nature reviews. Immunology, 2010 Jun 18, 3(4)
Innate IL-17-producing cells: the sentinels of the immune system.

[Abstract]The cytokine interleukin-17 (IL-17) has received considerable attention since the discovery of a distinct CD4(+) T helper (T(H)) cell subset that produces it, known as the T(H)17 cell subset. Despite the fact that most of the recent literature describes IL-17 as a T cell-secreted cytokine, much of the IL-17 released during an inflammatory response is produced by innate immune cells. In this Review, we explore the many innate immune cell populations that are an early source of IL-17 in response to stress, injury or pathogens. These early sources have been shown to have a central role in the initiation of IL-17-dependent immune responses, even before the first CD4(+)T cell sees its cognate antigen and initiates the T(H)17 cell developmental programme.

47: The Journal of investigative dermatology, 2010 Jun 17, 3(4)
Effective Narrow-Band UVB Radiation Therapy Suppresses the IL-23/IL-17 Axis in Normalized Psoriasis Plaques.

[Abstract]Narrow-band UVB radiation (NB-UVB) therapy offers a well-established treatment modality for psoriasis. However, despite the common use of this form of treatment, the mechanism of action of NB-UVB is not well understood. We studied a group of 14 patients with moderate-to-severe psoriasis treated with carefully titrated and monitored NB-UVB for 6 weeks. Lesional plaques were classified as normalized (n=8) or nonresponsive (n=6) based on their histological improvement and normalization. We characterized lesional myeloid dendritic cells (DCs) and T cells and their inflammatory mediators using immunohistochemistry and real-time PCR. NB-UVB suppressed multiple parameters of the IL-23/IL-17 pathway in normalized plaques, but not in nonresponsive plaques. NB-UVB decreased the numbers of CD11c(+) DCs, specifically CD1c(-)CD11c(+) "inflammatory" DCs, and their products, IL-20, inducible nitric oxide synthase, IL-12/23p40, and IL-23p19. Furthermore, effective NB-UVB suppressed IL-17 and IL-22 mRNAs, which strongly correlated with lesion resolution. Therefore, in addition to its known role in suppressing IFN-gamma production, NB-UVB radiation therapy can also target the IL-17 pathway to resolve psoriatic inflammation.Journal of Investigative Dermatology advance online publication, 17 June 2010; doi:10.1038/jid.2010.166.

48: Journal of neuroimmunology, 2010 Jun 14, 89(11)
Memory CD4(+)CD127(high) T cells from patients with multiple sclerosis produce IL-17 in response to myelin antigens.

[Abstract]Myelin-reactive T helper-17 cells are implicated in the pathogenesis of multiple sclerosis (MS). Here, we analyzed the reactivity of peripheral naive and memory conventional CD4(+)CD127(high) T cells (Tconv) of MS patients and healthy controls (HC) towards myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and tetanus toxoid (TT). Proliferative responses of Tconv cells towards MBP, MOG and TT were not significantly different between MS patients and HC. However, MBP and MOG but not TT reactive memory Tconv cells from MS patients, in contrast to HC, produced IL-17. These results suggest that myelin antigen reactive Th-17 cells are enriched in MS patients.

49: European journal of immunology, 2010 Jun 14, 89(11)
Promoting angiogenesis within the tumor microenvironment: The secret life of murine lymphoid IL-17-producing gammadelta T cells.

[Abstract]After two decades in the shadow of their alphabeta counterparts, gammadelta T cells have recently gathered significant attention following the discovery that gammadelta T cells produce interleukin-17 (IL-17) in various mouse models of infection and autoimmune disease. In contrast, the secretion of large amounts of Interferon-gamma (IFN-gamma) by gammadelta T cells has long been known, and has been tightly linked to their anti-tumor function. In this issue of the European Journal of Immunology, a study unexpectedly reports that the lymphoid gammadelta T cells that infiltrate tumor foci induced in the mouse skin produce very little IFN-gamma, but abundant IL-17. In fact, these gammadelta T cells are the major source of IL-17 within the tumor microenvironment, where they appear to promote angiogenesis, and thus tumor growth. This Commentarydiscussesthe relevance of these interesting findings in the context of the currently paradoxical pro- versus anti-tumor roles of IL-17 in cancer immunology.

50: Diabetes, 2010 Jun 14, 89(11)
Inflammatory tendencies and over production of IL-17 in the colon of young NOD mice are counteracted with diet change.

[Abstract]AbstractObjective Dietary factors influence diabetes development in the NOD mouse. Diet affects the composition of microbiota in the distal intestine, which may subsequently influence intestinal immune homeostasis. However, the specific effects of anti-diabetogenic diets on gut immunity and the explicit associations between intestinal immune disruption and type 1 diabetes onset remain unclear. Research design and methods Gut microbiota of NOD mice fed a conventional diet or ProSobee formula were compared using gas chromatography. Colonic lamina propria immune cells were characterised in terms of activation markers, cytokine mRNA and Th17 and Foxp3(+) T cell numbers using real time PCR and flow cytometry. Activation of diabetogenic CD4 T cells by purified B cells was assessed in both groups. Immune tolerance to autologous commensal bacteria was evaluated in vitro using thymidine-incorporation tests. Results Young NOD mice showed a disturbed tolerance to autologous commensal bacteria. Increased numbers of activated CD4 T cells and (CD11b(+)CD11c(+)) dendritic cels and elevated levels of Th17 cells and IL23 mRNA were moreover observed in colon lamina propria. These phenomena were abolished when mice were fed an antidiabetogenic diet. The antidiabetogenic diet also altered the expression levels of costimulatory molecules and the capacity of peritoneal B cells to induce insulin-specific CD4 T cell proliferation. Conclusions Young NOD mice show signs of subclinical colitis but the symptoms are alleviated by a diet change to an antidiabetogenic diet. Disrupted immune tolerance in the distal intestine may influence peritoneal cell pools and B-cell mediated activation of diabetogenic T cells.

51: Annals of the rheumatic diseases, 2010 Jun 11, 89(11)
Role of IL-17 in the Th1 systemic defects in rheumatoid arthritis through selective IL-12R{beta}2 inhibition.

[Abstract]BACKGROUND: /st> Patients with rheumatoid arthritis (RA) have a systemic Th1 defect associated with inflammation. OBJECTIVE: /st> To examine the hypothesis that interleukin 17 (IL-17) contributes to this defect. METHODS: /st> IL-17 effects on Th1 markers were examined on T-bet and interferon gamma (IFNgamma) expression in peripheral blood mononuclear cells (PBMCs) from patients with RA or healthy controls (HC). Receptor specificities were determined by analysis of the Th1-specific IL-12 receptor beta2 (IL-12Rbeta2), Th17-specific IL-23R and the common IL-12Rbeta1 chain expression. Effects of IL-17 or IFNgamma on IL-6, IL-1, IL-8, matrix metalloproteinase-8 (MMP-8) were measured by real-time RT-PCR in RA synovial cells. RESULTS: /st> RA PBMCs were less responsive to IL-12-induced IFNgamma than HC PBMCs. IL-12 hyporesponsiveness was increased by IL-17 treatment associated with a selective reduction in IL-12Rbeta2, but not IL-23R, IL-12Rbeta1 or T-bet, which was reversed with IL-17R inhibition. IL-17 inhibited IL-12Rbeta2 expression in developing Th1 cells. In RA synovial cells, IL-17 induced IL-6, IL-1, IL-8 and MMP-8, whereas IFNgamma had minimal or inhibitory effects. CONCLUSION: /st> In RA, IL-12 hyporesponsiveness is associated with IL-17R-mediated downregulation of IL-12Rbeta2 expression. IL-17 may reinforce Th17 lineage commitment and proinflammatory and destructive effects through Th1 inhibition and positive feedback effects in RA synovial cells. Anti-inflammatory effects of IL-17/IL-17R antagonism may include the restoration of protective Th1 responses.

52: European journal of immunology, 2010 Jun 10, 89(11)
EAE mediated by a non-IFN-gamma/non-IL-17 pathway.

[Abstract]Previous studies have shown that experimental autoimmune encephalomyelitis (EAE) can be elicited by the adoptive transfer of either IFN-gamma-producing (Th1) or IL-17-producing (Th17) myelin-specific CD4(+) T-cell lines. Paradoxically, mice deficient in either IFN-gamma or IL-17 remain susceptible to EAE following immunization with myelin antigens in CFA. These observations raise questions about the redundancy of IFN-gamma and IL-17 in autoimmune demyelinating disease mediated by a diverse, polyclonal population of autoreactive T cells. In the current study, we show that an atypical form of EAE, induced in C57BL/6 mice by the adoptive transfer of IFN-gamma-deficient effector T cells, required IL-17 signaling for the development of brainstem infiltrates. In contrast, classical EAE, characterized by predominant spinal cord inflammation, occurred in the combined absence of IFN-gamma and IL-17 signaling, but was dependent on GM-CSF and CXCR2. Our findings contribute to a growing body of data indicating that individual cytokines vary in their importance across different models of CNS autoimmunity.

53: Blood, 2010 Jun 10, 89(11)
Human fibroblasts support the expansion of IL-17 producing T-cells via up-regulation of IL-23 production by dendritic cells.

[Abstract]The initiation of immune responses is associated with the maturation of dendritic cells (DC) and their migration to draining lymph nodes. En route activated DC encounter cells of the tissue microenvironment such as fibroblasts. Since we have shown that DC interact with fibroblasts during immune responses we studied the impact of skin fibroblasts on human monocyte-derived DC function and subsequent human T cell (TC) differentiation. We show that fibroblasts support IL-23 secretion from DC preactivated by lipopolysaccharide (DC(act)) compared to LPS-activated DC alone. The underlying complex feedback-loop mechanism involves IL-1beta/TNFalpha (from DC(act)) which stimulate fibroblasts Prostaglandin E(2) production. Prostaglandin E(2), in turn, acts on DC(act) and increases their IL-23 release. Furthermore, fibroblast-stimulated DC(act) are far superior to DC(act) alone, in promoting the expansion of Th17 cells in a cox-2-, IL-23-dependent manner. Using CD4(+)CD45RO(+) memory TC and CD4(+)CD45RA(+) na?ve TC we showed that fibroblasts induce a phenotype of DC(act) that promote the expansion of Th17 cells. Moreover, in psoriasis, a prototypic immune response in which the importance of IL-23/Th17 is known, high expression of cox-2 in fibroblasts was observed. In conclusion, skin fibroblasts are involved in regulation of IL-23 production in DC and - as a result- of Th17 expansion.

54: Proceedings of the National Academy of Sciences of the United States of America, 2010 Jun 7, 476(3)
Identification of an IL-27/osteopontin axis in dendritic cells and its modulation by IFN-{gamma} limits IL-17-mediated autoimmune inflammation.

[Abstract]Dendritic cells (DCs) play a central role in determining the induction of T cell responses. IL-27 production by DCs favors induction of IL-10-producing regulatory T cells, whereas osteopontin (OPN) promotes pathogenic IL-17 T cell responses. The regulatory mechanisms in DCs that control these two cells types are not understood well. Here, we show that IFN-gamma induces IL-27 while inhibiting OPN expression in DCs both in vitro and in vivo and that engagement of IFN-gammaR expressed by DCs leads to suppression of IL-17 production while inducing IL-10 from T cells. DCs modified by IFN-gamma acquire IL-27-dependent regulatory function, promote IL-10-mediated T cell tolerance, and suppress autoimmune inflammation. Thus, our results identify a previously unknown pathway by which IFN-gamma limits IL-17-mediated autoimmune inflammation through differential regulation of OPN and IL-27 expression in DCs.

55: Cellular & molecular immunology, 2010 May 31, 184(11)
IL-17 signaling in host defense and inflammatory diseases.

[Abstract]Interleukin (IL)-17, the signature cytokine secreted by T helper (Th) 17 cells, plays important roles in host defense against extracellular bacterial infection and fungal infection and contributes to the pathogenesis of various autoimmune inflammatory diseases. Here we review the recent advances in IL-17-mediated functions with emphasis on the studies of IL-17-mediated signal transduction, providing perspective on potential drug targets for the treatment of autoimmune inflammatory diseases.Cellular & Molecular Immunology advance online publication, 31 May 2010; doi:10.1038/cmi.2010.27.

56: Journal of innate immunity, 2010 May 7, 285(19)
Emerging Role of IL-17 in Atherosclerosis.

[Abstract]The IL-23-IL-17 axis is emerging as a critical regulatory system that bridges the innate and adaptive arms of the immune system. Th17 cells have been linked to the pathogenesis of several chronic inflammatory and autoimmune diseases. However, the role of Th17 cells and IL-17 in various stages of atherogenesis remains poorly understood and is only beginning to be elucidated. While IL-17 is a predominantly proinflammatory cytokine, it has a pleiotropic function and it has been implicated both as an instigator in the pathogenesis of several inflammatory disorders as well as being protective in certain inflammatory disease models. Therefore, it is not surprising that the current literature is conflicting on the role of IL-17 during atherosclerotic lesion development. Various approaches have been used by several groups to discern the involvement of IL-17 in atherosclerosis. While one study found that IL-17 is protective against atherosclerosis, several other recent studies have suggested that IL-17 plays a proatherogenic role. Thus, the function of IL-17 remains controversial and awaits more direct studies to address the issue. In this review, we will highlight all the latest studies involving IL-17 and atherosclerosis, including both clinical and experimental research.

57: European journal of internal medicine, 2010 Jun, 21(3)
IL-17 in cutaneous lupus erythematosus.

[Abstract]BACKGROUND: Lupus erythematosus (LE) is a heterogeneous disease with broad clinical spectrum from cutaneous to visceral and systemic inflammation. IL-17 isoforms (IL-17A and IL-17F) are proinflammatory cytokines with unclear implications in lupus erythematosus pathogenesis. In this study we focused upon IL-17 in normal and modified lupus skin with a correlative study between local and serological expression. MATERIAL AND METHODS: 89 subjects were recruited and divided in 5 groups-10 patients with psoriasis (disease control group), 13 healthy controls, 26 with discoid chronic lupus (DLE), 23 with systemic lupus erythematosus (SLE) and 17 with subacute lupus erythematosus (SCLE). Blood samples and skin punched-biopsy specimens were performed. Serum IL-17A, IL-17F, and IL-23 concentrations were determined by ELISA. Skin IL-17A and CD4 expression were evaluated by immunohistochemistry. RESULTS: Immunohistochemical expression of IL-17A was higher in DLE, SCLE and SLE patients than in negative control subjects (all p<0.05). Serum IL-17A concentrations were higher in DLE and SLE patients than in negative controls (p<0.05). Serum IL-17A levels were similar in SCLE and negative controls (p>0.05). Serum IL-17F concentrations were higher in DLE, SCLE and SLE patients than in healthy controls (all p<0.05). In DLE, SCLE, SLE patients and healthy controls we observed comparable levels of IL-23 (p>0.05). Serum anti Ro antibodies correlate with IL-17A+ lymphocytes from SCLE lesion and SLE normal skin (all p<0.05). CONCLUSION: IL-17 isoforms (IL-17A and IL-17F) are implicated in SLE but also in DLE and SCLE immunopathogenesis.

58: European journal of immunology, 2010 May 18, 184(11)
CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC.

[Abstract]We have previously shown that human Th17 lymphocytes, are characterized by the selective expression of IL-23 receptor (IL-23R), CCR6, CD161, and the transcription factor RORC, and originate from a CD161+CD4+na?ve T-cell precursor in response to the combined activity of IL-1beta and IL-23. We show here that not only CD4+TCRalphabeta+, but also CD8+TCRalphabeta+, CD4(-)CD8(-) TCRalphabeta+, and CD4(-)-CD8(-) TCRgammadelta+circulating lymphocytes that produce IL-17 express the distinctive marker CD161 on their surface. In addition, we demonstrate that CD161 expression identifies CD8+and CD4-CD8- umbilical cord blood (UCB) T cells that already express RORC and IL-23R mRNA and that can be induced to differentiate into IL-17-producing cells in the presence of IL-1beta and IL-23. Finally, we provide evidence that UCB na?ve CD4+CD161(-) T cells, upon lentivirus-mediated transduction with RORC2, can acquire the ability to express IL-23R, IL-1RI, and CD161, as well as to produce IL-17.Taken together, these data allow to conclude that T-cell subsets able to produce IL-17, as well as precursors of IL-17-producing T cells, exhibit surface expression of CD161, and that this feature is at least in part RORC2-dependent.

59: Journal of immunology (Baltimore, Md. : 1950), 2010 Jun 1, 184(11)
Retraction: Reprogrammed FoxP3+ T Regulatory Cells Become IL-17+ Antigen-Specific Autoimmune Effectors In Vitro and In Vivo.

[Abstract]INTRODUCTION: The occurrence of severe sepsis may be associated with deficient pro-inflammatory cytokine production. Transforming growth factor beta-1 (TGFbeta-1) predominantly inhibits inflammation and may simultaneously promote IL-17 production. Interleukin-17 (IL-17) is a recently described pro-inflammatory cytokine, which may be important in auto-immunity and infection. We investigated the hypothesis that the onset of sepsis is related to differential TGFbeta-1 and IL-17 gene expression. METHODS: A prospective observational study in a mixed intensive care unit (ICU) and hospital wards in a university hospital. Patients (59) with severe sepsis; 15 patients with gram-negative bacteraemia but without critical illness and 10 healthy controls were assayed for TGFbeta-1, IL-17a, IL-17f, IL-6 and IL-1beta mRNA in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR and serum protein levels by ELISA. RESULTS: TGFbeta-1 mRNA levels are reduced in patients with bacteraemia and sepsis compared with controls (p=0.02). IL-6 mRNA levels were reduced in bacteraemic patients compared with septic patients and controls (p=0.008). IL-1beta mRNA levels were similar in all groups, IL-17a and IL-17f mRNA levels are not detectable in peripheral blood mononuclear cells. IL-6 protein levels were greater in patients with sepsis than bacteraemic and control patients (p<0.0001). Activated TGFbeta-1 and IL-17 protein levels were similar in all groups. IL-1beta protein was not detectable in the majority of patients. CONCLUSIONS: Down regulation of TGFbeta-1 gene transcription was related to the occurrence of infection but not the onset of sepsis. Interleukin-17 production in PBMC may not be significant in the human host response to infection.

60: PloS one, 2010, 5(5)
Modulation of IL-17 and Foxp3 expression in the prevention of autoimmune arthritis in mice.

[Abstract]BACKGROUND: Rheumatoid Arthritis (RA) is a chronic immune mediated disease associated with deregulation of many cell types. It has been reported that different T cell subsets have opposite effects in disease pathogenesis, in particular Th17 and Treg cells. METHODOLOGY AND FINDINGS: We investigated whether non-depleting anti-CD4 monoclonal antibodies, which have been reported as pro-tolerogenic, can lead to protection from chronic autoimmune arthritis in SKG mice--a recently described animal model of RA--by influencing the Th17/Treg balance. We found that non-depleting anti-CD4 prevented the onset of chronic autoimmune arthritis in SKG mice. Moreover, treated mice were protected from the induction of arthritis up to 60 days following anti-CD4 treatment, while remaining able to mount CD4-dependent immune responses to unrelated antigens. The antibody treatment also prevented disease progression in arthritic mice, although without leading to remission. Protection from arthritis was associated with an increased ratio of Foxp3, and decreased IL-17 producing T cells in the synovia. In vitro assays under Th17-polarizing conditions showed CD4-blockade prevents Th17 polarization, while favoring Foxp3 induction. CONCLUSIONS: Non-depleting anti-CD4 can therefore induce long-term protection from chronic autoimmune arthritis in SKG mice through reciprocal changes in the frequency of Treg and Th17 cells in peripheral tissues, thus shifting the balance towards immune tolerance.

61: Immunology, 2010 May 10, 50(3)
Interleukin (IL)-21-independent pathogen-specific CD8 T-cell expansion, and IL-21-dependent suppression of CD4(+) T-cell IL-17 production.

[Abstract]Summary Although interleukin-21 (IL-21) potently activates and controls the differentiation of immune cells after stimulation in vitro, the role for this pleiotropic cytokine during in vivo infection remains poorly defined. Herein, the requirement for IL-21 in innate and adaptive host defence after Listeria monocytogenes infection was examined. In the innate phase, IL-21 deficiency did not cause significant defects in infection susceptibility, or in the early activation of natural killer and T cells. In the adaptive phase, L. monocytogenes-specific CD8(+) T cells expand to a similar magnitude in IL-21-deficient mice compared with control mice. Interestingly, the IL-21-independent expansion of L. monocytogenes-specific CD8(+) T cells was maintained even in the combined absence of IL-12 and type I interferon (IFN) receptor. Similarly, L. monocytogenes-specific CD4(+) T cells expanded and produced similar levels of IFN-gamma regardless of IL-21 deficiency. Unexpectedly however, IL-21 deficiency caused significantly increased CD4(+) T-cell IL-17 production, and this effect became even more pronounced after L. monocytogenes infection in mice with combined defects in both IL-12 and type I IFN receptor that develop a T helper type 17-dominated CD4(+) T-cell response. Despite increased CD4(+) T-cell IL-17 production, L. monocytogenes-specific T cells re-expanded and conferred protection against secondary challenge with virulent L. monocytogenes regardless of IL-21 deficiency, or combined defects in IL-21, IL-12, and type I IFN receptor. Together, these results demonstrate non-essential individual and combined roles for IL-21, IL-12 and type I IFNs in priming pathogen-specific CD8(+) T cells, and reveal IL-21-dependent suppression of IL-17 production by CD4(+) T cells during in vivo infection.

62: Nature reviews. Rheumatology, 2010 May, 6(5)
New role for mast cells as IL-17-expressing effector cells in established RA.

[Abstract]CCR5 is a chemotactic mediator for inflammatory cells as well as regulatory T cells (Tregs). In this study, we investigated the role of CCR5 during infection with the fungal pathogen Histoplasma capsulatum. Mice lacking CCR5 or treated with an mAb to CCL4 had impaired infiltration of inflammatory cells to the lungs. Despite displaying an elevated fungal burden prior to activation of an adaptive immune response, CCL4-neutralized and CCR5(-/-) mice resolved infection more efficiently than controls. Accelerated fungal clearance was associated with a reduced number of Tregs in the lungs. Impaired trafficking was not solely responsible for the paucity of Tregs in the lungs, as proliferation of both CD4(+) T cells and Tregs was diminished in CCR5(-/-) lungs during infection. A reduced number of Tregs in CCR5(-/-) lungs was associated with a selective increase of Th17 cytokines, and neutralization of IL-17 increased Treg proliferation and consequently fungal burden in CCR5(-/-) mice. Thus, CCR5 dictates pathogen persistence by tightly regulating the balance between Treg and Th17 cells in H. capsulatum infection.

63: Journal of clinical immunology, 2010 May 2, 120(5)
The Polymorphism of IL-17 G-152A was Associated with Childhood Asthma and Bacterial Colonization of the Hypopharynx in Bronchiolitis.

[Abstract]OBJECTIVE: Interleukin (IL)-17 plays an important role in the pathogenesis of asthma. We investigated the association between single-nucleotide polymorphism (SNP) of IL-17 (rs2275913, IL-17 G-152A) and asthma-related traits. Its effect on IL-17 production was also attractive. METHODS: One hundred and sixty eight childhood asthmatic patients, 144 bronchiolitis patients, and 205 healthy controls were recruited in this study. SNP rs2275913 was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Peripheral blood mononuclear cells (PBMCs) from parts of healthy controls with different genotype were isolated and cultured with phytohaemagglutinin (PHA) for detection of IL-17 in the supernatants. RESULTS: SNP rs2275913 was associated with asthma (P = 0.03) in genotype frequency test. Children with homozygous A were 2.29 times more likely to have asthma than others (95% confidence interval 1.39-3.78, P = 0.001). The strength of associations was moderately higher by allergy comorbidity. Furthermore, SNP rs2275913 A allele was associated with abnormal lung function and serum total IgE in asthmatics, although the production of IL-17 by PHA-induced PBMC seemed to be not different among individuals with different genotypes. The distribution of SNP rs2275913 in bronchiolitis was marginally statistically different with controls and demonstrated a tendency close to that in asthma. Higher Streptococcus pneumoniae and Moraxella catarrhalis detection rates were shown in bronchiolitis patients with homozygous A allele than those with other genotypes (20.8% vs. 3.7%, P < 0.01 and 20.8% vs. 6.2%, P = 0.03). CONCLUSION: The preliminary results demonstrate that IL-17 SNP rs2275913 was associated with several asthma-related traits and confers genetic susceptibility to childhood asthma. It may be used to develop markers to assess the risk of asthma, especially in the bronchiolitis population. It may be a potential bridge to connect the bacterial colonization and the onset of asthma.

64: The British journal of dermatology, 2010 Apr 23, 184(9)
Novel findings of Langerhans cells and IL-17 expression in relation to the acrosyringium and pustule in palmoplantar pustulosis.

[Abstract]Summary Backgound Palmoplantar pustulosis (PPP) is a chronic and intensely inflammatory skin disease with pustules, erythema and scaling localised to the palms and soles. To date, no specific treatment is known. Earlier findings indicate the acrosyringium as the target for the inflammation. Objectives To identify specific features of the PPP inflammatory cell infiltrate and mediators of inflammation, which might provide insight into the pathogenesis and possible future treatment of the disease. Patients/Methods Skin biopsies were taken from 23 patients with typical PPP (23 from involved skin and 7 from non-involved skin) and from 18 healthy controls (10 non-smokers, 8 smokers). Cell infiltrates and inflammation mediators were studied with immunohistochemistry. Results A strong inflammation was observed in lesional skin of PPP. Our main findings of Langerhans cells and IL-17 close to or in the acrosyringium differs from what is seen in psoriasis vulgaris. Other inflammatory cells such as CD4+, CD8+, regulatory T cells and CD11a+ cells were also accumulated close to the sweat duct in epidermis and papillary dermis. More CD4+, CD8+, Langerhans cells, plasmacytoid dendritic cells and a higher proportion of T(REG)/CD3+ cells were seen in non-involved palmar skin from PPP patients compared to healthy controls. Conclusion Our novel findings indicate that the inflammation in PPP is initiated by the "stand-by" innate immune system at the acrosyringium.

65: American journal of respiratory and critical care medicine, 2010 Apr 22, 184(9)
Resolution of Allergic Airway Inflammation and Airway Hyperreactivity is Mediated by IL-17 Producing {gamma}{delta}T Cells.

[Abstract]RATIONALE: gammadeltaT lymphocytes are enriched within the epithelial microenvironment where they are thought to maintain homeostasis and limit immunopathology. gammadeltaT cells are postulated to exert a regulatory influence during acute allergic airway disease, but the mechanism is unknown. Although regulation of allergic airway disease has been attributed to IL-17 producing Th17 cells, we have found that gammadeltaT cells represent the major source of IL-17 in the allergic lung. OBJECTIVES: The aim of this study was to determine the contribution of these IL-17 producing gammadeltaT cells to regulation of allergic airway inflammation. METHODS: Flow cytometry revealed that IL-17 producing gammadeltaT cells are more prevalent than IL-17(+)alphabetaT cells (Th17) in a murine model of ovalbumin induced allergic inflammation. MEASUREMENTS: Transfer of gammadeltaT cells at the peak of acute allergic responses ameliorated AHR with a corresponding acceleration in the resolution of eosinophilic and Th2 driven inflammation. Conversely, functional blockade of gammadeltaT cells led to exacerbation of injury. Neither treatment changed pulmonary Th17 cell numbers. Moreover, transfer of Th17 cells had no effect on disease outcome. Importantly, IL-17 deficient gammadeltaT cells were unable to promote resolution of injury. MAIN RESULTS: These data identify IL-17 producing gammadeltaT cells as key regulators of the allergic response in vivo. CONCLUSIONS: This unfolds a new perspective for the understanding of gammadeltaT cell function with regard to innate regulation of the adaptive immune responses, emphasising that resolution of responses are important in determining the outcome of acute inflammatory episodes as well as for maintenance of tissue integrity and homeostasis.

66: The Journal of investigative dermatology, 2010 Apr 22, 184(9)
TGFbeta1-Induced Inflammation in Premalignant Epidermal Squamous Lesions Requires IL-17.

[Abstract]Overexpression of transforming growth factor-beta1 (TGFbeta1) in the normal epidermis can provoke an inflammatory response, but whether this occurs within a developing tumor is not clear. To test this, we used an inducible transgenic mouse to overexpress TGFbeta1 in premalignant squamous lesions. Within 48 hours of TGFbeta1 induction, there was an increase in IL-17 production by both CD4(+) and gammadelta(+) T cells, together with increased expression of T-helper-17 (Th17)-polarizing cytokines. Induction of TGFbeta1 in premalignant primary keratinocytes elevated the expression of proinflammatory and Th17-polarizing cytokines, and the keratinocyte-conditioned media caused IL-17 production by naive T cells that was dependent on T-cell TGFbeta1 signaling. Microarray analysis showed significant upregulation of proinflammatory genes 2 days after TGFbeta1 induction, and this was followed by increased MPO(+), F4/80(+), and CD8(+) cells in tumors, increased CD8(+) effectors and IFNgamma(+) cells in skin-draining LNs, and tumor regression. In parallel, the percentage of tumor CD11b(+)Ly6G(+) neutrophils was reduced. Neutralization of IL-17 blocked TGFbeta1-induced CD11b(+) Ly6G(-) tumor infiltration but did not alter the reduction of neutrophils or tumor regression. Thus, TGFbeta1 overexpression causes IL-17-dependent and IL-17-independent changes in the premalignant tumor inflammatory microenvironment.Journal of Investigative Dermatology advance online publication, 22 April 2010; doi:10.1038/jid.2010.92.

67: Journal of immunology (Baltimore, Md. : 1950), 2010 Apr 21, 184(9)
Secretion of IFN-{gamma} but Not IL-17 by CD1d-Restricted NKT Cells Enhances Rejection of Skin Grafts Expressing Epithelial Cell-Derived Antigen.

[Abstract]NKT cells are key regulators of autoimmunity, tumor immune surveillance, and the immune response to pathogens. The role of NKT cells in regulating adaptive immunity to cutaneous Ags is largely unknown. This study explores the role of CD1d-restricted NKT cells in cross-priming of CD8 effector T cells to OVA expressed in epithelial keratinocytes (K5mOVA transgenic mouse). In a skin grafting model, we show that NKT cells enhance the rejection of K5mOVA skin grafts by promoting generation of OVA-specific CD8 effector T cells in the skin-draining lymph nodes. This is associated with a decrease in the proportion of both Th17 cells and IL-17-producing NKT cells within the lymph node, thereby inducing a Th1-biased response by increasing the ratio of IFN-gamma to IL-17 production. Administration of a strong agonist ligand (alpha-galactosylceramide) for NKT cells induced higher levels of local IFN-gamma production, enhancing the rate of K5mOVA graft rejection. Thus, NKT cells can promote adaptive immunity to cell-associated Ag expressed in skin by local regulation of IFN-gamma production in secondary lymphoid tissue during cross-priming of effector CD8 T cells.

68: Journal of dental research, 2010 Apr 16, 78(5)
IL-17 in Sera from Patients with Aggressive Periodontitis.

[Abstract]Interleukin-17 (IL-17), the prototype cytokine produced by the Th17 subset of T-helper cells, plays a role in inflammatory responses, autoimmunity, and antimicrobial responses in a variety of infectious and inflammatory diseases. In view of the inflammatory nature and severity of aggressive periodontitis, we hypothesized that IL-17 might be detected in sera from patients with aggressive periodontitis. We used ELISA to measure IL-17 serum concentrations from 67 periodontally healthy (NP) individuals and from 53 patients with localized (LAgP) and 49 patients with generalized (GAgP) aggressive periodontitis. IL-17 was barely detectable in sera from periodontally healthy individuals (1.9 +/- 2.0 pg/mL), but was present at significantly higher concentrations in sera from those with LAgP (7.6 +/- 2.2 pg/mL) and GAgP (17.1 +/- 2.3 pg/mL). Multivariate analyses demonstrated associations of IL-17 concentrations with periodontal attachment loss, but not with current smoking. Therefore, Th17 responses may be characteristic of AgP, and IL-17 may play a role in the pathogenesis of aggressive periodontitis.

69: International immunopharmacology, 2010 Apr 14, 184(8)
Downregulation of IL-17 and IFN-gamma in the optic nerve by beta-elemene in experimental autoimmune encephalomyelitis.

[Abstract]BACKGROUND: beta-elemene is a natural antitumor plant drug, Beneficial effects of beta-elemene therapy have been demonstrated in some kinds of tumor clinically. Especially, it has been found to pass through the blood brain barrier easily. Other reports have indicated that immune disorder appeared in some tumors usually can be seen in demyelinating diseases including multiple sclerosis and experimental autoimmune encephalomyelitis. However, no information regarding the effects of beta-elemene therapy on the T helper cell subsets, Th1 or Th17 cells in experimental autoimmune encephalomyelitis has been found. METHODS AND FINDINGS: We first determined morphologically that beta-elemene therapy markedly suppressed the inflammation in experimental autoimmune encephalomyelitis optic nerve. We then determined the effect in vivo of beta-elemene on Treg cells and Th17Th1 cells. We found that beta-elemene treatment modulated immune balance in both the periphery and the inflamed optic nerve by promoting a less downregulation in Treg cells, inhibiting Th17 and Th1 polarization. CONCLUSIONS: Taken together, our finding reveals an important new locus where beta-elemene induces substantial protection in experimental autoimmune encephalomyelitis optic nerve through signaling to several critical subsets of immune cells that reside in the peripheral and central nervous system.

70: European journal of immunology, 2010 Apr 15, 50(2)
Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor via promoting angiogenesis.

[Abstract]Based on the evidence that IL-17 is a key cytokine involved in various inflammatory diseases, we explored the critical role of IL-17-producing gammadelta T cells for tumor development in tumor-bearing mouse model. IL-17(-/-) mice exhibited a significant reduction of tumor growth, concomitantly with the decrease of vascular density at lesion area, indicating a pro-tumor property of IL-17. Among tumor-infiltrating lymphocytes (TIL),gammadelta T cells were the major cellular source of IL-17. Analysis of TCR repertoires in TIL-gammadelta T cells showed that circulating gammadelta T cells but not skin resident Vgamma5(+)gammadelta T cells produced IL-17. Neutralizing antibodies against IL-23, IL-6, and TGF-beta, which were produced within the tumor microenvironment, inhibited the induction of IL-17-producing gammadelta T cells. IL-17 production by tumor-infiltrating gammadelta T cells was blocked by anti-gammadeltaTCR or anti-NKG2D antibodies, indicating that these ligands expressed within the tumor microenvironment are involved in gammadeltaT-cell activation. The IL-17-producing TIL-gammadelta T cells exhibited reduced levels of perforin mRNA expression, but increased levels of COX-2 mRNA expression. Together, our findings support the novel concept that IL-17-producing gammadelta T cells generated in response to tumor microenvironment act as tumor-promoting cells by inducing angiogenesis.

71: Blood, 2010 Apr 15, 50(2)
Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma.

[Abstract]Elevated cytokines in bone marrow (BM) micro-environment (IL-6, TGF-beta, & IL-1beta) may play an important role in observed immune dysfunction in multiple myeloma (MM). As IL-6 and TGF-beta are important for the generation of T(H)17 cells, we observed a significantly elevated baseline and induced frequency of T(H)17 cells in peripheral blood (PBMC) and BM mononuclear cells (BMMC) from MM patients compared to healthy donors. We observed significant increase in levels of serum IL-17, IL-21, IL-22 and IL-23 in blood and BM in MM compared with healthy donor. We also observed that the myeloma PBMC following T(H)17 polarization significantly induced IL-1alpha, IL-13, and IL-17 and IL-23 production compared with healthy donor PBMCs. We next observed that IL-17 promotes myeloma cell growth and colony formation via IL-17 receptor, adhesion to bone-marrow stromal cells (BMSC) as well as increased growth in vivo in murine xenograft model of human MM. Additionally; we have observed that combination of IL-17 and IL-22 significantly inhibited the production of T(H)1-mediated cytokines, including IFN-gamma, by healthy donor PBMCs. In conclusion, IL-17-producing T(H)17 cells play an important role in MM pathobiology and may be an important therapeutic target for anti-MM activity and to improve immune function.

72: Transplantation, 2010 Apr 13, 184(8)
Local IL-17 Production and a Decrease in Peripheral Blood Regulatory T Cells in an Animal Model of Bronchiolitis Obliterans.

[Abstract]BACKGROUND.: Recently, it has been reported that Th17 contributes to allograft rejection after transplantation. We investigated the alteration of Th17 and regulatory T cells (Treg) distribution in an animal model of bronchiolitis obliterans following ectopic tracheal transplantation model. METHODS.: Tracheal grafts from B6 mice transplanted into subcutaneous sites of C3H mice. Allografts were histologically evaluated, and expressions of CD4, CD8, CD25, CD28, CD127, CD152 and Foxp3, and intracellular interleukin (IL)-4, -6, -17, and interferon-gamma, in peripheral blood lymphocytes were analyzed. Tracheal graft IL-6 and -17 mRNA expression was assessed using a quantitative reverse-transcriptase polymerase chain reaction. All the data in allogenic transplantation was compared with those in isograft controls. In addition, the effect of IL-6 neutralization on the allograft was evaluated with histopathology and the IL-17 mRNA expression. RESULTS.: Treg was significantly lower in peripheral blood of allogenic mice, whereas no significant difference in Th17 in the CD4 T-cell population was observed after allogenic or isogenic transplantation. Locoregional histologic examination revealed the presence of IL-6-producing lymphocytes and endothelium in the allograft, and the luminal obliteration by fibroblast proliferation. Both IL-6 and IL-17 mRNA levels were elevated in the allograft. Severity of tracheal obliteration and IL-17 mRNA level was significantly suppressed in the IL-6 neutralized allografts. CONCLUSIONS.: After allograft in a mouse bronchiolitis obliterans model, IL-17 production increases locally without an alteration in peripheral blood Th17 cells, whereas peripheral Tregs decreases. Th17 cells, which can be regulated by IL-6 stimulation, may play a role in posttransplantation rejection of the allograft.

73: Diabetes research and clinical practice, 2010 Apr 12, 184(8)
Unregulated IL-23/IL-17 immune response in autoimmune diseases.

[Abstract]INTRODUCTION: Type 1A diabetes (T1D) is an autoimmune disease resulting from the selective destruction of pancreatic beta cells by T cells most likely due to interaction of environmental and genetic factors. The CD4((+)) T cells, largely implicated in this disease, comprise different subsets; based on the cytokines they produce. These subsets include Th1, Th2, regulatory T cells and another population of recently described T cells called Th17 cells. Increased expression of interleukin 17 (IL-17) has been detected in sera and in target tissues of patients with various autoimmune diseases. The differentiation of Th17 cells from na?ve T cells appears to involve signals from TGF-beta, IL-6, IL-21, IL-1beta and IL-23. IL-23, a member of the IL-12 family, which activate the effector function of Th17 cells to promote inflammatory responses. In animal models, IL-23 is involved in the development of autoimmune diabetes. In humans, it seems to cause multi-organ inflammation, contributing to rheumatoid arthritis, inflammatory bowel disease and celiac disease manifestations. CONCLUSIONS: The discovery that certain autoimmune disorders might be largely mediated by an unregulated IL-23/IL-17 response has important implications for the development of novel therapies for these diseases.

74: Cellular & molecular immunology, 2010 Apr 12, 184(8)
Interleukin-17 and its expanding biological functions.

[Abstract]Interleukin-17 (IL-17) and IL-17-producing cells have been shown to play important roles in inflammation and the immune response. IL-17 is believed to be mainly produced by T helper 17 (Th17) cells, a unique helper T-cell subset different from Th1 and Th2 cells. Other subsets of T cells such as gammadeltaT and natural killer T (NKT) cells have also been found to produce IL-17 in response to innate stimuli. IL-17 acts as a proinflammatory cytokine that can induce the release of certain chemokines, cytokines, matrix metalloproteinases (MMPs) and antimicrobial peptides from mesenchymal and myeloid cells. This leads to the expansion and accumulation of neutrophils in the innate immune system and links innate and adaptive immunity in vivo. Furthermore, increasing evidence indicates that IL-17 and IL-17-producing cells are involved in the pathogenesis of various diseases such as allergies, autoimmune diseases, allograft transplantation and even malignancy. They may also play protective roles in host defense against infectious diseases and promote induction of cytotoxic T lymphocyte (CTL) responses against cancer. Targeting of the IL-17 axis is under investigation for the treatment of inflammatory disorders.Cellular & Molecular Immunology advance online publication, 19 April 2010; doi:10.1038/cmi.2010.21.

75: Kidney international, 2010 Apr 7, 11(1)
Mycophenolic acid suppresses granulopoiesis by inhibition of interleukin-17 production.

[Abstract]Mycophenolic acid is a commonly used immunosuppressant after organ transplantation and in autoimmune diseases; however, myelosuppression is a major complication despite its largely favorable side-effect profile. Mycophenolic acid targets inosine monophosphate dehydrogenase, which is essential for T-cell proliferation. The T-cell cytokine interleukin-17 (IL-17 or IL-17A) and its receptor maintain normal neutrophilic granulocyte numbers in mice by induction of granulocyte-colony-stimulating factor. To test whether mycophenolic acid induces neutropenia by inhibiting IL-17-producing T cells, we treated C57Bl/6 mice with mycophenolate-mofetil (the orally available pro-drug) and found a dose-dependent decrease in blood neutrophils. This myelosuppressive effect was completely abolished in mice that lack the IL-17 receptor. Mycophenolic acid delayed myeloid recovery after bone marrow transplantation and decreased the percentage of IL-17-producing T cells in the spleen and thymus, and inhibited IL-17 production in human and mouse T cells in vitro. Injection of IL-17 during mycophenolic acid treatment overcame the suppression of the circulating neutrophil levels. Our study shows that mycophenolic acid suppresses neutrophil production by inhibiting IL-17 expression, suggesting that measurement of this interleukin might be useful in estimating the risk of neutropenia in clinical settings.Kidney International advance online publication, 7 April 2010; doi:10.1038/ki.2010.84.

76: BMC genomics, 2010 Apr 7, 11(1)
Genome-wide comparison between IL-17 and combined TNF-alpha/ IL-17 induced genes in primary murine hepatocytes.

[Abstract]ABSTRACT: BACKGROUND: Cytokines such as TNF-alpha and IL-1beta are known for their contribution to inflammatory processes in liver. In contrast, the cytokine IL-17 has not yet been assigned a role in liver diseases. IL-17 can cooperate with TNF-alpha to induce a synergistic response on several target genes in different cell lines, but no data exist for primary hepatocytes. To enhance our knowledge on the impact of IL-17 alone and combined with TNF-alpha in primary murine hepatocytes a comprehensive microarray study was designed. IL-1beta was included as this cytokine is suggested to act in a similar manner as the combination of TNF-alpha and IL-17, especially with respect to its role in mRNA stabilization. RESULTS: The present microarray analysis demonstrates that primary murine hepatocytes responded to IL-17 stimulation by upregulation of chemokines and genes, which are functionally responsible to increase and sustain inflammation. Cxcl2, Nfkbiz and Zc3h12a were strongly induced, whereas the majority of the genes were only very moderately up-regulated. Promoter analysis revealed involvement of NF-kappaB in the activation of many genes. Combined stimulation of TNF-alpha/IL-17 resulted in enhanced induction of gene expression, but significantly synergistic effects could be applied only to a few genes, such as Nfkbiz, Cxcl2, Zc3h12 and Steap4. Comparison of the gene expression profile obtained after stimulation of TNF-alpha/IL-17 versus IL-1beta proposed an "IL-1beta-like effect" of the latter cytokine combination. Moreover, evidence was provided that modulation of mRNA stability may be a major mechanism by which IL-17 regulates gene expression in primary hepatocytes. This assumption was exemplarily proven for Nfkbiz mRNA for the first time in hepatocytes. Our studies also suggest that RNA stability can partially be correlated to the existence of AU rich elements, but further mechanisms like the RNase activity of the up-regulated Zc3h12a have to be considered. CONCLUSIONS: Our microarray analysis gives new insights in IL-17 induced gene expression in primary hepatocytes highlighting the crosstalk with the NF-kappaB signaling pathway. Gene expression profile suggests IL-17 alone and in concert with TNF-alpha a role in sustaining liver inflammatory processes. IL-17 might exceed this function by RNA stabilization.

77: The Journal of clinical investigation, 2010 Apr 1, 24(4)
IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice.

[Abstract]Staphylococcus aureus is the most common cause of skin and soft tissue infections, and rapidly emerging antibiotic-resistant strains are creating a serious public health concern. If immune-based therapies are to be an alternative to antibiotics, greater understanding is needed of the protective immune response against S. aureus infection in the skin. Although neutrophil recruitment is required for immunity against S. aureus, a role for T cells has been suggested. Here, we used a mouse model of S. aureus cutaneous infection to investigate the contribution of T cells to host defense. We found that mice deficient in gammadelta but not alphabeta T cells had substantially larger skin lesions with higher bacterial counts and impaired neutrophil recruitment compared with WT mice. This neutrophil recruitment was dependent upon epidermal Vgamma5+ gammadelta T cell production of IL-17, but not IL-21 and IL-22. Furthermore, IL-17 induction required IL-1, TLR2, and IL-23 and was critical for host defense, since IL-17R-deficient mice had a phenotype similar to that of gammadelta T cell-deficient mice. Importantly, gammadelta T cell-deficient mice inoculated with S. aureus and treated with a single dose of recombinant IL-17 had lesion sizes and bacterial counts resembling those of WT mice, demonstrating that IL-17 could restore the impaired immunity in these mice. Our study defines what we believe to be a novel role for IL-17-producing epidermal gammadelta T cells in innate immunity against S. aureus cutaneous infection.

78: Mucosal immunology, 2010 Mar 31, 39(5)
Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection.

[Abstract]Pigtail macaques (PTMs) rapidly progress to AIDS after simian immunodeficiency virus (SIV) infection. Given the strong association between human immunodeficiency virus (HIV) and SIV disease progression and microbial translocation and immune activation, we assessed whether high basal levels of immune activation and microbial translocation exist in PTMs. We found that before SIV infection, PTMs had high levels of microbial translocation that correlated with significant damage to the structural barrier of the gastrointestinal tract. Moreover, this increased microbial translocation correlated with high levels of immune activation and was associated with high frequencies of interleukin-17-producing T cells. These data highlight the relationship among mucosal damage, microbial translocation and systemic immune activation in the absence of SIV replication, and underscore the importance of microbial translocation in the rapid course of disease progression in SIV-infected PTMs. Furthermore, these data suggest that PTM may be an ideal model to study therapeutic interventions aimed at decreasing microbial translocation-induced immune activation.Mucosal Immunology advance online publication 31 March 2010. doi:10.1038/mi.2010.14.

79: Journal of immunology (Baltimore, Md. : 1950), 2010 Mar 31, 39(5)
IL-17 Amplifies Human Contact Hypersensitivity by Licensing Hapten Nonspecific Th1 Cells to Kill Autologous Keratinocytes.

[Abstract]Th17 is a newly identified lineage of effector T cells involved in autoimmunity and immune responses to pathogens. We demonstrate in this study the pathogenic role of IL-17-producing CD4(+) T lymphocytes in allergic contact dermatitis (ACD) to skin-applied chemicals. IL-17(+) T cells infiltrate ACD reactions and predominantly distribute at the site of heavy spongiosis. Skin IL-17(+) T cells were functionally and phenotypically heterogeneous: although pure Th17 prevailed in ACD skin, hapten responsiveness was restricted to Th1/IL-17 (IFN-gamma(+)IL-17(+)) and Th0/IL-17 (IFN-gamma(+)IL-17(+)IL-4(+)) fractions, and to lesser extent Th2/IL-17 cells. In the IFN-gamma-dominated ACD environment, IL-17-releasing T cells affect immune function of keratinocytes by promoting CXCL8, IL-6, and HBD-2 production. In addition, compared with Th1, supernatants from Th1/IL-17 T cells were much more efficient in inducing ICAM-1 expression on keratinocytes and keratinocyte-T cell adhesiveness in vitro. As a consequence, exposure to combined IFN-gamma and IL-17 rendered keratinocytes susceptible to ICAM-1-dependent Ag nonspecific T cell killing. Thus, IL-17 efficiently amplifies the allergic reaction by rendering virtually all of the T lymphocytes recruited at the site of skin inflammation capable to directly contribute to tissue damage.

80: International journal of obesity (2005), 2010 Mar 30, 39(5)
The IL-23/IL-17 axis may be important in obesity-associated cancer by way of the activation of multiple signal pathways.

[Abstract]OBJECTIVES: During the last decade research has focused on the RANK-RANKL-OPG (Receptor Activator of Nuclear factor KappaB-Receptor Activator of Nuclear factor KappaB Ligand-Osteoprotegerin) pathway that is currently considered the final common route to bone and joint remodeling. The potential role of novel additional mediators has been highlighted by several reports. This review focuses on the recent information about the pathophysiology of the Wingless (Wnt) pathway and interleukin-17 (IL-17) in relation of their role in bone and joint remodeling. METHODS: An extensive internet search was performed (PubMed) from 1998 and onward using the following keywords: Wnt, bone remodeling, bone, rheumatic diseases, rheumatoid arthritis, IL-17, Th17, osteoblastogenesis, and osteoclastogenesis. RESULTS: Several members of the Wnt pathway play an important role in bone remodeling. Recent experimental data indicate a key role for Dickkopf-1, a soluble inhibitor of the Wnt pathway, in bone remodeling. Increased Dickkopf-1 levels are linked to bone resorption and decreased levels to new bone formation. Low-density lipoprotein receptor-related protein-5, the main receptor that mediates Wnt signaling, plays a critical role in bone mass regulation. Gain-of-function mutations of lipoprotein receptor-related protein-5 cause high bone mass phenotypes, whereas loss-of-function mutations are linked to severe osteoporosis. IL-17 is a proinflammatory cytokine that is produced by a recently described T-cell subset, known as Th17 cells. Evidence suggests that IL-17 is a critical mediator of joint destruction in animal models of arthritis. IL-17 blockade has beneficial effects on murine arthritis, a fact that points to the direction of this cytokine as a potential therapeutic target in human inflammatory arthritides as well. CONCLUSIONS: The available data suggest that mediators in these 2 biologic systems are critical in joint remodeling and may be appropriate targets in the treatment of bone and joint abnormalities that characterize a variety of inflammatory arthritides and bone diseases.

81: Journal of immunology (Baltimore, Md. : 1950), 2010 Mar 29, 39(5)
Langerhans Cells Prime IL-17-Producing T Cells and Dampen Genital Cytotoxic Responses following Mucosal Immunization.

[Abstract]Langerhans cells (LCs) are dendritic cells (DCs) localized in stratified epithelia, such as those overlaying skin, buccal mucosa, and vagina. The contribution of LCs to the promotion or control of immunity initiated at epithelial sites remains debated. We report in this paper that an immunogen comprising OVA linked to the B subunit of cholera toxin, used as delivery vector, was efficient to generate CTLs after vaginal immunization. Using Lang-EGFP mice, we evaluated the contribution of distinct DC subsets to the generation of CD4 and CD8 T cell responses. We demonstrate that the vaginal epithelium, unlike the skin epidermis, includes a minor population of LCs and a major subset of langerin(-) DCs. Intravaginally administered Ag is taken up by LCs and langerin(-) DCs and carried up to draining lymph nodes, where both subsets prime CD8 T cells, unlike blood-derived DCs, although with distinct capabilities. LCs prime CD8 T cells with a cytokine profile dominated by IL-17, whereas Lang(-) DCs induce IFN-gamma-producing T cells. Using Lang-DTR-EGFP mice to ensure a transient ablation of LCs, we found that these cells not only are dispensable for the generation of genital CTL responses but also downregulate these responses, by a mechanism that may involve IL-10 and IL-17 cytokines. This finding has implications for the development of mucosal vaccines and immunotherapeutic strategies designed for the targeting of DCs.

82: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, 2010 Mar 29, 39(5)
Phosphoinositide 3-kinase {delta} inhibitor suppresses IL-17 expression in a murine asthma model.

[Abstract]Phosphoinositide 3-kinases (PI3Ks) contribute to the pathogenesis of asthma by regulating the activation of inflammatory mediators, inflammatory cell recruitment, and immune cell function. Recent findings have indicated that PI3Ks also regulate the expression of interleukin (IL)-17, which has been introduced as an important cytokine involved in airway inflammation.In the present study, we investigated a role of PI3Kdelta in the regulation of IL-17 expression in allergic airway disease using a murine model of asthma.After ovalbumin (OVA) inhalation, administration of a selective p110delta inhibitor, IC87114, significantly attenuated airway infiltration of total cells, lymphocytes, neutrophils, and eosinophils as well as airway hyperresponsiveness and decreased the increase in IL-17 protein and mRNA expression. Moreover, IC87114 reduced levels of IL-4, IL-5, and IL-13, expression of keratinocyte chemoattractant protein and mRNA, and nuclear factor-kappaB (NF-kappaB) activity. In addition, a NF-kappaB inhibitor, BAY 11-7085 substantially reduced the increase in IL-17 protein levels. Our results also showed that inhibition of IL-17 activity with an anti-IL-17 antibody remarkably reduced airway inflammation and hyperresponsiveness.These findings suggest that inhibition of the p110delta signalling pathway suppresses IL-17 expression through regulation of NF-kappaB activity and thus has therapeutic potential in asthma.

83: Cytokine, 2010 Mar 27, 39(5)
IL-17 is elevated in cerebrospinal fluids in bacterial meningitis in children.

[Abstract]Bacterial meningitis has a poor prognosis and neurologic complications. The present study aimed to investigate the cytokine/chemokine network in cerebrospinal fluid (CSF) from children with bacterial meningitis and aseptic meningitis. Interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1beta, were measured simultaneously in CSF supernatants. We found that, IL-17 was significantly elevated in CSF with bacterial meningitis. We believe that IL-17 plays a key role in neutrophil infiltration into CSF and neuronal protection in bacterial meningitis.

84: Blood, 2010 Mar 25, 115(12)
Does IL-17 suppress tumor growth?

[Abstract]There is now substantial evidence that the cytokine interleukin-17 orchestrates the accumulation of neutrophils in mammals and thereby contributes to host defense. However, the role of IL-17 in controlling neutrophil turnover is not fully understood. Here, we demonstrate that IL-17 stimulates the apoptosis of mouse neutrophils and, simultaneously, the release of the microbicidal compound, myeloperoxidase. IL-17 also stimulates mouse macrophages to phagocytose aged neutrophils and latex beads, and it induces an increase in a soluble form of the phagocytic receptor, lectin-like oxidized low-density lipoprotein receptor-1 as well. In contrast, IL-17 does not markedly increase the release of the archetype neutrophil-recruiting cytokine, macrophage inflammatory protein-2 in mouse macrophages. Importantly, IL-17 also stimulates the phagocytosis of latex beads in human monocyte-derived macrophages. Thus, IL-17 bears the potential to control both phagocytosis and neutrophil turnover during activation of host defense.

85: Respiratory medicine, 2010 Mar 23, 115(12)
Increased serum IL-17 is an independent risk factor for severe asthma.

[Abstract]BACKGROUND: IL-17 expression was found to be associated with many inflammatory diseases in humans, such as rheumatoid arthritis, asthma, systemic lupus erythematosus and allograft rejection and many in vitro studies have indicated a proinflammatory function for IL-17. OBJECTIVE: Prognostic value of increased serum IL-17 in asthma patients. METHODS: Serum IL-17 (ELISA) was measured in 85 asthma patients (pts), mean age 46.99 +/- 14.1 years, 61% females, 23 mild persistent, 26 moderate persistent and 36 severe persistent asthma. Using multiple regression analysis (STATISTICA 7), increased serum IL-17 (>20 pg/ml) was tested as risk factor for severe asthma in comparison with "traditional" risk factors: smoke, NSAID intolerance, obesity, chronic rhinosinusitis, blood eosinophilia, FEV(1) at baseline < 50% predicted (low FEV(1)). RESULTS: Medium serum IL-17 values were 14.21 pg/ml in mild asthma, 12.22 pg/ml in moderate asthma and 24.72 pg/ml in severe asthma. IL-17 values > 20 pg/ml were encountered in 3(13%) mild asthma pts (p < 0.001 vs. severe asthma), 2(8%) moderate asthma pts. (p < 0.001 vs. severe asthma), and in 11(31%) severe asthma pts. For severe asthma multiple regression analysis revealed as independent risk factors IL-17 (p = 0.000290), NSAID intolerance (p = 0.000585) and low FEV(1) (p = 0.000059). CONCLUSIONS: IL-17 is increased in severe asthma compared to mild/moderate forms of the disease and values above 20 pg/ml are an independent risk factor for severe asthma.

86: Journal of immunology (Baltimore, Md. : 1950), 2010 Mar 24, 115(12)
CCR5 Dictates the Equilibrium of Proinflammatory IL-17+ and Regulatory Foxp3+ T Cells in Fungal Infection.

[Abstract]CCR5 is a chemotactic mediator for inflammatory cells as well as regulatory T cells (Tregs). In this study, we investigated the role of CCR5 during infection with the fungal pathogen Histoplasma capsulatum. Mice lacking CCR5 or treated with an mAb to CCL4 had impaired infiltration of inflammatory cells to the lungs. Despite displaying an elevated fungal burden prior to activation of an adaptive immune response, CCL4-neutralized and CCR5(-/-) mice resolved infection more efficiently than controls. Accelerated fungal clearance was associated with a reduced number of Tregs in the lungs. Impaired trafficking was not solely responsible for the paucity of Tregs in the lungs, as proliferation of both CD4(+) T cells and Tregs was diminished in CCR5(-/-) lungs during infection. A reduced number of Tregs in CCR5(-/-) lungs was associated with a selective increase of Th17 cytokines, and neutralization of IL-17 increased Treg proliferation and consequently fungal burden in CCR5(-/-) mice. Thus, CCR5 dictates pathogen persistence by tightly regulating the balance between Treg and Th17 cells in H. capsulatum infection.

87: Inflammatory bowel diseases, 2010 Mar 22, 39(5)
4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease.

[Abstract]BACKGROUND:: Dihydroorotate dehydrogenase (DHODH) is a key enzyme involved in pyrimidine biosynthesis. DHODH is a known target for the treatment of autoimmune diseases. 4SC-101 is a novel immunosuppressive drug that inhibits DHODH. A goal of our study was to examine the in vitro effects of 4SC-101 on IL-17 production by mononuclear cells. In addition, we evaluated the efficacy of 4SC-101 against acute TNBS (2,4,6-tritrobenzene sulfonic acid) and chronic dextran sodium sulfate (DSS)-induced colitis in mice. METHODS:: Peripheral blood mononuclear cells (PBMCs) from healthy human donors were used to evaluate cellular proliferation and cytokine (IL-17, TNF-alpha) production. The oral effects of 4SC-101 (100 or 200 mg/kg) were examined following induction of chronic colitis by the administration of 3% DSS (4 cycles) to Balb/c mice. Morphometric and histological indices of colitis were evaluated as indicators of drug efficacy. 4SC-101 was also administered for 6 days after the intracolonic administration of TNBS (20 mg in 50% ethanol) to female Balb/c mice. The colons were analyzed for overall macroscopic damage, ulceration, total length, distal segment weight, MPO activity, and histological pathology as indicators for the effectiveness of 4SC-101. RESULTS:: In vitro, 4SC-101 is a potent inhibitor of human DHODH, inhibits lymphocyte proliferation, and uniquely blocks phytohemagglutinin-stimulated IL-17 production by lymphocytes. In vivo, oral administration of 4SC-101 effectively improved both chronic DSS and acute TNBS colitis in mice. In these colitis models the overall efficacy profile of 4SC-101 was similar to that of dexamethasone. CONCLUSIONS:: 4SC-101 is a novel immunosuppressive drug with excellent potential for the treatment of intestinal inflammation. (Inflamm Bowel Dis 2010).

88: Infection and immunity, 2010 Mar 15, 74(4)
Chlamydia T cell antigens formulated with the adjuvant DDA/TDB induce immunity against infection which correlates with a high frequency of IFN-{gamma}/TNF-{alpha} and IFN-{gamma}/IL-17 double positive CD4+ T cells.

[Abstract]Major impediments to developing a Chlamydia vaccine lie in identifying immunologically relevant T cell antigens and delivery in a manner to stimulate protective immunity. Using an immunoproteomic approach, we previously identified three immunodominant Chlamydia T cell antigens (PmpG-1, PmpE/F-2 and RplF). Because RplF has high homology to a human ortholog, it may not be suitable for human vaccine development. In this study we therefore evaluated protection against Chlamydia genital tract infection in C57BL/6 mice immunized with Chlamydia specific membrane proteins, PmpG-1, PmpE/F-2, MOMP (as a reference) or a combination formulated with three adjuvants, CpG-ODN, AbISCO or DDA/TDB. The results show that immunization with the CpG-ODN formulation failed to provide protection against Chlamydia infection; AbISCO formulation conferred moderate protection and DDA/TDB formulation showed the highest degree of protective efficacy. The combination of PmpG-1, PmpE/F-2 and MOMP protein formulated with DDA/TDB exhibited the greatest degree of protection among all vaccine groups studied. Moreover, this vaccine combination also engendered significant protection in BALB/c mice with a different MHC background. We measured cell-mediated immune cytokine responses in mice immunized with PmpG-1 mixed with the three adjuvants. The results demonstrate that mice immunized with DDA/TDB formulation induced the strongest IFN-gamma and IL-17 responses characterized by the highest frequency of IFN-gamma/TNF-alpha and IFN-gamma/IL-17 double positive CD4+ T cells. In conclusion, a Chlamydia vaccine based on the recombinant proteins PmpG-1, PmpE/F-2 and MOMP delivered in a DDA/TDB adjuvant conferred protection against infection that correlated with IFN-gamma/TNF-alpha and IFN-gamma/IL-17 double positive CD4+ T cells.

89: Journal of immunology (Baltimore, Md. : 1950), 2010 Mar 12, 184(6)
IL-17-Mediated Monocyte Migration Occurs Partially through CC Chemokine Ligand 2/Monocyte Chemoattractant Protein-1 Induction.

[Abstract]Rheumatoid arthritis (RA) is a chronic inflammatory disease that is mediated, in part, by proinflammatory factors produced by RA synovial tissue (ST) fibroblasts and macrophages, resulting in monocyte migration from the blood to the ST. To characterize the potential role of IL-17 in monocyte migration, RA synovial fibroblasts and macrophages were activated with IL-17 and examined for the expression of monocyte chemokines. The two potentially important monocyte chemoattractants identified were CCL20/MIP-3alpha and CCL2/MCP-1, which were significantly induced in RA synovial fibroblasts and macrophages. However, in vivo, only CCL2/MCP-1 was detectable following adenovirus IL-17 injection. We found that IL-17 induction of CCL2/MCP-1 was mediated by the PI3K, ERK, and JNK pathways in RA ST fibroblasts and by the PI3K and ERK pathways in macrophages. Further, we show that neutralization of CCL2/MCP-1 significantly reduced IL-17-mediated monocyte recruitment into the peritoneal cavity. We demonstrate that local expression of IL-17 in ankle joints was associated with significantly increased monocyte migration and CCL2/MCP-1 levels. Interestingly, we show that RA synovial fluids immunoneutralized for IL-17 and CCL2/MCP-1 have similar monocyte chemotaxis activity as those immunoneutralized for each factor alone. In short, CCL2/MCP-1 produced from cell types present in the RA joint, as well as in experimental arthritis, may be responsible, in part, for IL-17-induced monocyte migration; hence, these results suggest that CCL2/MCP-1 is a downstream target of IL-17 that may be important in RA.

90: Journal of immunology (Baltimore, Md. : 1950), 2010 Mar 12, 184(6)
IL-17 Promotes p38 MAPK-Dependent Endothelial Activation Enhancing Neutrophil Recruitment to Sites of Inflammation.

[Abstract]Neutrophilic inflammation plays an important role in lung tissue destruction occurring in many chronic pulmonary diseases. Neutrophils can be recruited to sites of inflammation via the action of the cytokine IL-17. In this study, we report that IL-17RA and IL-17RC mRNA expression is significantly increased in asthmatic bronchoscopic biopsies and that these receptors are not only expressed on epithelial and inflammatory cells but also on endothelial cells. IL-17 potently stimulates lung microvascular endothelial cells to produce chemoattractants (CXCL8 and derivatives of the 5-lipoxygenase pathway) that selectively drive neutrophil but not lymphocyte chemotaxis. Moreover, IL-17 promotes endothelial activation by inducing the expression of endothelial adhesion markers (E-selectin, VCAM-1, and ICAM-1) in a p38 MAPK-dependent manner. This increased expression of adhesion molecules stimulates the trans-endothelial migration of neutrophils, as well as the transmigration of HT-29 colon carcinoma cells, suggesting a further role in promoting lung metastasis. Finally, IL-17 increased neutrophil adhesion to the endothelium in vivo as determined by intravital microscopy of mice cremaster muscle. Overall, our results demonstrate that IL-17 is a potent activator of the endothelium in vivo leading to neutrophil infiltration. Therefore, preventing neutrophil recruitment by blocking the action of IL-17 on endothelial cells may prove to be highly beneficial in diseases in which neutrophilic inflammation plays a key role.

91: Stem cells (Dayton, Ohio), 2010 Mar 10, 184(6)
Phagocytosis of Apoptotic Cells Modulates Mesenchymal Stem Cells Osteogenic Differentiation to Enhance IL-17 and RANKL Expression on CD4+ T cells.

[Abstract]Osteogenic differentiation of mesenchymal stem cells (MSC) is important to homeostatic bone remodeling. Infiltration of mesenchymal progenitor cells to inflamed joints have been reported in collagen-induced arthritis murine model and rheumatoid arthritis (RA) patients. Therapeutic application of MSC in RA has been suggested and under investigation. However, the underlying mechanisms on what trigger the migration of MSC from bone marrow (BM) to inflamed joints and how MSC acts in the joints remains elusive. As hemopoietic stem cells and MSC act reciprocally and excessive apoptotic cells (AC) are observed in the BM of RA patients, we hypothesize that AC may alter MSC osteogenic differentiation resulting in bone erosion in RA. In this study, we demonstrated for the first time that MSC were able to phagocytose AC and this phagocytosis enhanced MSC osteogenic differentiation. AC-treated MSC under osteogenic differentiation expressed CXCR4 and CXCR5 which might enable them to migrate towards the inflamed joints. In addition, AC-treated MSC secreted interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1) and RANTES, which might induce chemotaxis of CD4+ T cells to the inflamed joints. Interestingly, by co-culturing AC-treated MSC under osteogenic differentiation with CD4+ T cells, T helper (Th) 17 cells development was significantly enhanced and these Th17 cells promoted osteoclasts formation and bone resorption. Furthermore, the induction of Th17 cells was dependent on increased IL-6 production from MHC class II-expressing AC-treated MSC under osteogenic differentiation. This data provide a novel insight on the role of AC in modulating MSC osteogenic differentiation and function in inflammatory bone diseases.

92: The Journal of biological chemistry, 2010 Mar 10, 184(6)
Induction of neutrophil gelatinase-associated lipocalin expression by co-stimulation with IL-17 and TNF-{alpha} is controlled by I{kappa}B-{zeta} but neither by C/EBP-{beta} nor by C/EBP-{delta}

[Abstract]Neutrophil gelatinase-associated lipocalin (NGAL) is a siderophore-binding antimicrobial protein that is upregulated in epithelial tissues during inflammation. We demonstrated previously that NGAL is strongly upregulated by IL-1beta in an NF-kappaB-dependent manner but not by TNF-alpha, another potent activator of NF-kappaB. This is due to an IL-1beta-specific synthesis of the NF-kappaB-binding co-factor IkappaB-zeta, which is essential for NGAL induction. We demonstrate here that NGAL is strongly induced by stimulation with TNF-alpha in the presence of IL-17, a pro-inflammatory cytokine produced by the newly discovered subset of CD4+ T helper cells, TH-17. In contrast to the murine NGAL orthologue, 24p3/lipocalin 2, we found no requirement for C/EBP-beta or C/EBP-delta for NGAL induction by IL-17 and TNF-alpha as neither siRNAs against the two C/EBP mRNAs nor mutation of the C/EBP-sites in the NGAL promoter abolished IL-17 and TNF-alpha-induced upregulation of NGAL. NGAL-induction is governed solely by NF-kappaB and its co-factor IkappaB-zeta. This was demonstrated by a pronounced reduction in the amount of NGAL mRNA and NGAL protein synthesized in cells treated with siRNA against IkappaB-zeta and a total lack of activation of an NGAL promoter construct with a mutated NF-kappaB site. As IL-17-stimulation stabilizes the IkappaB-zeta transcript, we propose a model where TNF-alpha induces activation and binding of NF-kappaB to the promoters of both the IkappaB-zeta and the NGAL genes but induce only transcription of IkappaB-zeta. Co-stimulation with IL-17 leads to accumulation of IkappaB-zeta mRNA and IkappaB-zeta protein, which can bind to NF-kappaB on the NGAL promoter and thus induce NGAL expression.

93: American journal of reproductive immunology (New York, N.Y. : 1989), 2010 Mar 4, 184(6)
Accumulation of IL-17-Positive Cells in Decidua of Inevitable Abortion Cases.

[Abstract]Citation Nakashima A, Ito M, Shima T, Bac ND, Hidaka T, Saito S. Accumulation of IL-17-positive cells in decidua of inevitable abortion cases. Am J Reprod Immunol 2010 Problem Th17 cells, a new subset of helper T cells, have been focused on as a producer pro-inflammatory cytokines. It is, however, still unknown how Th17 cells affect pregnancy outcome. We investigated the expression of IL-17-producing cells in human spontaneous abortion. Method of study IL-17 expression was analyzed in decidual tissues among normal pregnancy, missed abortion, and inevitable abortion cases by immunohistochemistry and flow cytometry. Results IL-17(+) cells were accumulated in decidua and were detected in decidual CD4(+) T cells and few decidual CD8(+) T cells in spontaneous abortion cases. The number of decidual IL-17(+) cells in inevitable abortion cases involving active genital bleeding was significantly higher than that in normal pregnancy cases (P < 0.05). On the other hand, there were no significant differences in the numbers of decidual IL-17(+) cells between missed abortion cases and normal pregnancy subjects. Furthermore, the number of IL-17(+) cells was positively correlated with the number of neutrophils in spontaneous abortion cases. Conclusion IL-17(+) cells might be involved in the induction of inflammation in the late stage of abortion, but not in the early stage of abortion.

94: Acta neurologica Scandinavica, 2010 Mar 4, 184(6)
Interleukin-17 and interleukin-23 are elevated in serum and cerebrospinal fluid of patients with ALS: a reflection of Th17 cells activation?

[Abstract]Rentzos M, Rombos A, Nikolaou C, Zoga M, Zouvelou V, Dimitrakopoulos A, Alexakis T, Tsoutsou A, Samakovli A, Michalopoulou M, Evdokimidis J. Interleukin-17 and interleukin-23 are elevated in serum and cerebrospinal fluid of patients with ALS: a reflection of Th17 cells activation? Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2010.01333.x. (c) 2010 The Authors Journal compilation (c) 2010 Blackwell Munksgaard. Background - There is evidence that immunological factors may involved in pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS). Th17 cells are characterized by predominant production of IL-17 and are suggested to be crucial in destructive autoimmunity. Interleukin-23 (IL-23) appears to play a supporting role in the continued stimulation and survival of Th17. Patients and methods - We measured by enzyme-like immunosorbent assay (ELISA) serum and cerebrospinal fluid (CSF) levels of IL-17 and IL-23 in 22 patients with ALS and 19 patients with other non-inflammatory neurological disorders (NIND) studied as a control group. IL-17 and IL-23 serum and CSF levels were also correlated with duration of the disease, the disability level and the clinical subtype of the disease onset in patients with ALS. Results - IL-17 and IL-23 serum levels were higher in patients with ALS as compared with patients with NIND (P = 0.015 and P = 0.002 respectively). IL-17 and IL-23 CSF levels were also increased in patients with ALS (P = 0.0006 and P = 0.000001 respectively). IL-17 and IL-23 levels were not correlated with disease duration, disability scale or clinical subtype of the disease onset in ALS patients. Conclusions - Our findings suggest that these molecules may be involved in the pathogenetic mechanisms acting as potential markers of Th17 cells activation in ALS.

95: Journal of leukocyte biology, 2010 Mar, 87(3)
Response to "The Src/PI3K/Akt pathway may play a key role in the production of IL-17 in obesity".

[Abstract]The role of immune responses in tumor development is a central issue for tumor biology and immunology. IL-17 is an important cytokine for inflammatory and autoimmune diseases. Although IL-17-producing cells are detected in cancer patients and tumor-bearing mice, the role of IL-17 in tumor development is controversial, and mechanisms remain to be fully elucidated. In the current study, we found that the development of tumors was inhibited in IL-17R-deficient mice. A defect in IFN-gammaR increased tumor growth, whereas tumor growth was inhibited in mice that were deficient in both IL-17R and IFN-gammaR compared with wild-type animals. Further experiments showed that neutralization of IL-17 by Abs inhibited tumor growth in wild-type mice, whereas systemic administration of IL-17 promoted tumor growth. The IL-17R deficiency increased CD8 T cell infiltration, whereas it reduced the infiltration of myeloid-derived suppressor cells (MDSCs) in tumors. In contrast, administration of IL-17 inhibited CD8 T cell infiltration and increased MDSCs in tumors. Further analysis indicated that IL-17 was required for the development and tumor-promoting activity of MDSCs in tumor-bearing mice. These data demonstrate that IL-17-mediated responses promote tumor development through the induction of tumor-promoting microenvironments at tumor sites. IL-17-mediated regulation of MDSCs is a primary mechanism for its tumor-promoting effects. The study provides novel insights into the role of IL-17 in tumor development and has major implications for targeting IL-17 in treatment of tumors.

96: Journal of leukocyte biology, 2010 Mar, 87(3)
The Src/PI3K/Akt pathway may play a key role in the production of IL-17 in obesity.

[Abstract]The role of immune responses in tumor development is a central issue for tumor biology and immunology. IL-17 is an important cytokine for inflammatory and autoimmune diseases. Although IL-17-producing cells are detected in cancer patients and tumor-bearing mice, the role of IL-17 in tumor development is controversial, and mechanisms remain to be fully elucidated. In the current study, we found that the development of tumors was inhibited in IL-17R-deficient mice. A defect in IFN-gammaR increased tumor growth, whereas tumor growth was inhibited in mice that were deficient in both IL-17R and IFN-gammaR compared with wild-type animals. Further experiments showed that neutralization of IL-17 by Abs inhibited tumor growth in wild-type mice, whereas systemic administration of IL-17 promoted tumor growth. The IL-17R deficiency increased CD8 T cell infiltration, whereas it reduced the infiltration of myeloid-derived suppressor cells (MDSCs) in tumors. In contrast, administration of IL-17 inhibited CD8 T cell infiltration and increased MDSCs in tumors. Further analysis indicated that IL-17 was required for the development and tumor-promoting activity of MDSCs in tumor-bearing mice. These data demonstrate that IL-17-mediated responses promote tumor development through the induction of tumor-promoting microenvironments at tumor sites. IL-17-mediated regulation of MDSCs is a primary mechanism for its tumor-promoting effects. The study provides novel insights into the role of IL-17 in tumor development and has major implications for targeting IL-17 in treatment of tumors.

97: The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology, 2010 Feb 25, 220(4)
IL-17-producing T helper cells and Th17 Cytokines in human airways exposed to endotoxin.

[Abstract]Previous studies on mouse models have indicated that IL-17 and IL-17-producing T helper cells are important for pulmonary host defence against gram-negative bacteria. Human correlates to these findings have not yet been demonstrated.The aim of this study was to determine whether IL-17-producing T helper cells are present and whether IL-17 and other Th17-associated cytokines are involved in the immunological response to endotoxin in human airways.We performed segmental exposure to endotoxin and contra-lateral exposure to vehicle in the lungs of healthy volunteers, with subsequent bronchoalveolar lavage 12h or 24h after exposure, to study local changes in cytokines and inflammatory cells.Endotoxin exposure increased protein concentrations of IL-17, IL-22 and their down stream effector molecules human beta-defensin-2 and IL-8/CXCL8 in bronchoalveolar lavage. T helper cells with the capacity to produce IL-17 were found among the bronchoalveolar lavage cells and expression of IL-17mRNA correlated with expression of the transcription factor RORC2. Moreover, endotoxin increased the number of neutrophils, macrophages and IL-17-producing T cells, as well as the concentration of Th17-regulating cytokines IL-21 and IL-23.In conclusion, IL-17-producing T helper cells are present and IL-17 as well as other Th17-associated cytokines are involved in the immunological response to endotoxin in human airways.

98: Journal of clinical immunology, 2010 Feb 23, 220(4)
The IL-17 Family Cytokines in Immunity and Disease.

[Abstract]INTRODUCTION: Accumulating evidence suggests that the interleukin (IL)-17 cytokines are major players in the immune response to foreign pathogens. In addition, the pathogeneses of a number of inflammatory diseases have been linked to uncontrolled expression of these cytokine pathways. DISCUSSION: Genetic and biochemical analyses have elucidated the cellular and molecular events triggered by these proteins during an inflammatory response. While significant efforts have been placed on understanding the functions of IL-17A, IL-17F, and IL-17E, the significance of the other family members, IL-17B-D, in inflammation remains to be determined. CONCLUSION: This review will focus on the cellular sources, target cell/receptors that are utilized by these cytokines to control pathogenesis, and the therapeutic potential of targeting these pathways to treat inflammatory disorders.

99: Journal of immunology (Baltimore, Md. : 1950), 2010 Feb 19, 220(4)
IL-17 Contributes to Angiogenesis in Rheumatoid Arthritis.

[Abstract]Angiogenesis is an early and a critical event in the pathogenesis of rheumatoid arthritis (RA). Neovascularization is dependent on endothelial cell activation, migration and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. In this study, we document a novel role of IL-17 in mediating angiogenesis. Local expression of IL-17 in mouse ankles increases vascularity. We further demonstrate that IL-17 is angiogenic by showing its ability to promote blood vessel growth in Matrigel plugs in vivo. Additionally, IL-17, in concentrations present in the RA joint, induces human lung microvascular endothelial cell (HMVEC) migration mediated through the PI3K/AKT1 pathway. Furthermore, suppression of the PI3K pathway markedly reduces IL-17-induced tube formation. We also show that both IL-17-induced HMVEC chemotaxis and tube formation are mediated primarily through IL-17 receptor C. Neutralization of either IL-17 in RA synovial fluids or IL-17 receptor C on HMVECs significantly reduces the induction of HMVEC migration by RA synovial fluid. Finally, RA synovial fluid immunoneutralized with anti-IL-17 and antivascular endothelial growth factor does not reduce HMVEC migration beyond the effect detected by immunodepleting each factor alone. These observations identify a novel function for IL-17 as an angiogenic mediator in RA, supporting IL-17 as a therapeutic target in RA.

100: PLoS neglected tropical diseases, 2010, 4(2)
IL-17 Produced during Trypanosoma cruzi Infection Plays a Central Role in Regulating Parasite-Induced Myocarditis.

[Abstract]BACKGROUND: Chagas disease is a neglected disease caused by the intracellular parasite Trypanosoma cruzi. Around 30% of the infected patients develop chronic cardiomyopathy or megasyndromes, which are high-cost morbid conditions. Immune response against myocardial self-antigens and exacerbated Th1 cytokine production has been associated with the pathogenesis of the disease. As IL-17 is involved in the pathogenesis of several autoimmune, inflammatory and infectious diseases, we investigated its role during the infection with T. cruzi. METHODOLOGY/PRINCIPAL FINDINGS: First, we detected significant amounts of CD4, CD8 and NK cells producing IL-17 after incubating live parasites with spleen cells from normal BALB/c mice. IL-17 is also produced in vivo by CD4(+), CD8(+) and NK cells from BALB/c mice on the early acute phase of infection. Treatment of infected mice with anti-mouse IL-17 mAb resulted in increased myocarditis, premature mortality, and decreased parasite load in the heart. IL-17 neutralization resulted in increased production of IL-12, IFN-gamma and TNF-alpha and enhanced specific type 1 chemokine and chemokine receptors expression. Moreover, the results showed that IL-17 regulates T-bet, RORgammat and STAT-3 expression in the heart, showing that IL-17 controls the differentiation of Th1 cells in infected mice. CONCLUSION/SIGNIFICANCE: These results show that IL-17 controls the resistance to T. cruzi infection in mice regulating the Th1 cells differentiation, cytokine and chemokine production and control parasite-induced myocarditis, regulating the influx of inflammatory cells to the heart tissue. Correlations between the levels of IL-17, the extent of myocardial destruction, and the evolution of cardiac disease could identify a clinical marker of disease progression and may help in the design of alternative therapies for the control of chronic morbidity of chagasic patients.

101: Investigative ophthalmology & visual science, 2010 Feb 17, 7(2)
p38{alpha} MAP Kinase controls IL-17 synthesis in Vogt-Koyanagi-Harada Syndrome and Experimental Autoimmune Uveitis (EAU).

[Abstract]Purpose: Interleukin 17 (IL-17) was recently described as the main cytokine involved in autoimmune diseases, being responsible for the initial influx of leukocytes into tissues. Vogt-Koyanagi-Harada (VKH) disease is a significant cause of non-infectious blindness. Herein we aimed at unraveling the involvement of IL-17 in VKH pathology and in experimental autoimmune uveitis, focusing on the signaling pathways involved in IL-17 synthesis. Methods: Mice were immunized with 161-180 peptide and PTx. Draining lymph node cells, harvested 21 days after immunization, were cultured in the presence or absence of p38alpha MAPK inhibitor (SB203580) and assayed for cytokine production and quantification of CD4+IL-17+ cells. Mice received intraocular injections of SB203580 and disease severity was evaluated by histological examination of the enucleated eyes at day 21. CD4+ lymphocytes from MSK-1/2-deficient mice, human CD4+ cells silenced with MSK1 siRNA or PBMC from VKH patients were cultured in the presence or absence of p38alpha MAPK inhibitor and then assayed for IL-17, IFN-gamma and IL-4 production. Results: The inhibition of p38alpha MAPK fully blocked the synthesis of IL-17 by PBMC from VKH patients and lymphocytes from EAU mice. The absence of MSK1/2 gene resulted in failure to produce IL-17 by murine and human lymphocytes. Interestingly, intraocular injections of SB203580 in EAU mice did not suppress development of disease. Conclusions: Our data show that p38alpha MAPK-MSK1/2 are involved in the control of IL-17 synthesis by CD4+ T cells, that inhibition of p38alpha MAPK in vitro suppresses IL-17 synthesis but that inhibition of this kinase in vivo did not protect from EAU.

102: Shock (Augusta, Ga.), 2010 Feb 10, 133(2-4)
Differential effects of IL-17 pathway in disseminated candidiasis and zymosan-induced multiple organ failure.

[Abstract]The role of the IL-17 pathway in antifungal host defense is controversial. Several studies suggested that IL-17 is crucial for the protection against Candida infection, while other studies reported that IL-17 may contribute to inflammatory pathology and worsening of fungal disease. To address these discrepancies, we assessed the differential role of IL-17 pathway in two models of fungal sepsis: intravenous infection with live C. albicans in which fungal growth is the main cause of mortality, and zymosan-induced multiple organ failure in which the inflammatory pathology drives the mortality. Firstly, IL-17 receptor deficient (IL-17RA-/-) mice showed increased mortality and higher fungal loads in the kidneys in the model of disseminated candidiasis, partly due to lower neutrophil recruitment in the IL-17RA-/- mice. Secondly, IL-17RA-/- mice were not protected against the multi-organ failure induced by zymosan. These data demonstrate that IL-17 does not have a major contribution to the inflammatory pathology leading to organ failure in fungal sepsis, and support the concept that the IL-17 pathway is protective in antifungal host defense.

103: Cell host & microbe, 2010 Feb 18, 7(2)
Microbial Colonization Drives Expansion of IL-1 Receptor 1-Expressing and IL-17-Producing gamma/delta T Cells.

[Abstract]IL-17 cytokine production by the Th17 T cell subset is regulated by intestinal commmensals. We show that microbial colonization also regulates innate IL-17 production. A population of CD62L(-) gamma/delta T cells, in particular a lineage expressing the IL-1 receptor 1 (IL-1R1), can be quickly activated by microbes to produce IL-17. Antibiotic treatment and monocolonization of mice suggest that specific commensals-but not metronidazole-sensitive anaerobes like Bacteroides species-are required for maintaining IL-1R1(+) gamma/delta T cells. Signaling through the guanine nucleotide exchange factor VAV1, but not through Toll-like receptors or antigen presentation pathways, is essential for inducing IL-1R1(+) gamma/delta T cells. Furthermore, IL-1R1(+) gamma/delta T cells are a potential source of IL-17 that can be activated by IL-23 and IL-1 in both infectious and noninfectious settings in vitro and in vivo. Thus, commensals orchestrate the expansion of phenotypically distinct gammadelta T cells, and innate immunity is a three-way interaction between host, pathogens, and microbiota.

104: Immunity, 2010 Jan 29, 32(1)
Response: Characteristics of IL-17-Producing gammadelta T Cells.

[Abstract]IL-17 is an important cytokine in the physiopathology of rheumatoid arthritis (RA). However, its participation in the genesis of nociception during RA remains undetermined. In this study, we evaluated the role of IL-17 in the genesis of articular nociception in a model of antigen (mBSA)-induced arthritis. We found that mBSA challenge in the femur-tibial joint of immunized mice induced a dose- and time-dependent mechanical hypernociception. The local IL-17 concentration within the mBSA-injected joints increased significantly over time. Moreover, co-treatment of mBSA challenged mice with an antibody against IL-17 inhibited hypernociception and neutrophil recruitment. In agreement, intraarticular injection of IL-17 induced hypernociception and neutrophil migration, which were reduced by the pre-treatment with fucoidin, a leukocyte adhesion inhibitor. The hypernociceptive effect of IL-17 was also reduced in TNFR1(-/-) mice and by pre-treatment with infliximab (anti-TNF antibody), a CXCR1/2 antagonist or by an IL-1 receptor antagonist. Consistent with these findings, we found that IL-17 injection into joints increased the production of TNF-alpha, IL-1beta and CXCL1/KC. Treatment with doxycycline (non-specific MMPs inhibitor), bosentan (ET(A)/ET(B) antagonist), indomethacin (COX inhibitor) or guanethidine (sympathetic blocker) inhibited IL-17-induced hypernociception. IL-17 injection also increased PGE(2) production, MMP-9 activity and COX-2, MMP-9 and PPET-1 mRNA expression in synovial membrane. These results suggest that IL-17 is a novel pro-nociceptive cytokine in mBSA-induced arthritis, whose effect depends on both neutrophil migration and various pro-inflammatory mediators, as TNF-alpha, IL-1beta, CXCR1/2 chemokines ligands, MMPs, endothelins, prostaglandins and sympathetic amines. Therefore, it is reasonable to propose IL-17 targeting therapies to control this important RA symptom.

105: Immunity, 2010 Jan 29, 32(1)
Response: Characteristics of IL-17-Producing gammadelta T Cells.

[Abstract]IL-17 is an important cytokine in the physiopathology of rheumatoid arthritis (RA). However, its participation in the genesis of nociception during RA remains undetermined. In this study, we evaluated the role of IL-17 in the genesis of articular nociception in a model of antigen (mBSA)-induced arthritis. We found that mBSA challenge in the femur-tibial joint of immunized mice induced a dose- and time-dependent mechanical hypernociception. The local IL-17 concentration within the mBSA-injected joints increased significantly over time. Moreover, co-treatment of mBSA challenged mice with an antibody against IL-17 inhibited hypernociception and neutrophil recruitment. In agreement, intraarticular injection of IL-17 induced hypernociception and neutrophil migration, which were reduced by the pre-treatment with fucoidin, a leukocyte adhesion inhibitor. The hypernociceptive effect of IL-17 was also reduced in TNFR1(-/-) mice and by pre-treatment with infliximab (anti-TNF antibody), a CXCR1/2 antagonist or by an IL-1 receptor antagonist. Consistent with these findings, we found that IL-17 injection into joints increased the production of TNF-alpha, IL-1beta and CXCL1/KC. Treatment with doxycycline (non-specific MMPs inhibitor), bosentan (ET(A)/ET(B) antagonist), indomethacin (COX inhibitor) or guanethidine (sympathetic blocker) inhibited IL-17-induced hypernociception. IL-17 injection also increased PGE(2) production, MMP-9 activity and COX-2, MMP-9 and PPET-1 mRNA expression in synovial membrane. These results suggest that IL-17 is a novel pro-nociceptive cytokine in mBSA-induced arthritis, whose effect depends on both neutrophil migration and various pro-inflammatory mediators, as TNF-alpha, IL-1beta, CXCR1/2 chemokines ligands, MMPs, endothelins, prostaglandins and sympathetic amines. Therefore, it is reasonable to propose IL-17 targeting therapies to control this important RA symptom.

106: Fish & shellfish immunology, 2010 Feb 5, 133(2-4)
Isolation of seven IL-17 family genes from the Japanese pufferfish Takifugu rubripes.

[Abstract]In humans, the IL-17 family is composed of six members (A-F). The A, E and F forms have been extensively studied in numerous mammalian species. However, there are few reports regarding IL-17 expression in teleost. In this study, IL-17 family genes were isolated from the Japanese pufferfish (Fugu) and their structure and expression profile were analyzed. Screening of the Fugu genome database revealed the existence of five scaffolds containing IL-17 family homologous genes. Scaffold_1 contained three IL-17 family homologues including IL-17A/F1, 2 and C2, and IL-17A/F1 and 2 located in tandem. This was similar to the IL-17 A/F1 and 2 genes in zebrafish and to human IL-17A and F. Other scaffolds 38, 143 and 430, contained IL-17 family homologous genes that were identical to IL-17D, A/F3 and C1 in Fugu, respectively. Moreover, IL-17 family homologues on scaffold_264 included a novel type of IL-17 family genes in teleost. These isolates contained four cysteine residues that were involved in the formation of a typical cysteine knot consisting of two disulphide linkages. However, IL-17A/F2 did not demonstrate any conservation at the second and fourth cysteine residues. The tissue distribution of the Fugu IL-17 family genes was also found to differ. In particular, IL-17 family genes were highly expressed in the head kidney and gill. Moreover, expression of IL-17 family genes was significantly up-regulated in the lipopolysaccharide-stimulated head kidney. These results suggested that Fugu IL-17 family members were involved in inflammatory responses.

107: European journal of immunology, 2010 Apr, 40(4)
Complement C5a regulates IL-17 by affecting the crosstalk between DC and gammadelta T cells in CLP-induced sepsis.

[Abstract]Complement 5a (C5a) and Interleukin-17 (IL-17) are two important inflammatory mediators in sepsis. Here we studied the mechanisms underlying regulation of IL-17 by anaphylatoxin C5a. We found that C5a blockade increased the survival rate of mice following cecal ligation and puncture (CLP)-induced sepsis and decreased IL-17 expression in vivo. IL-17 was secreted mainly by gammadelta T cells in this model. Importantly, our data suggest that C5a participates in the regulation of IL-17 secretion by gammadelta T cells. Dendritic cells (DC) were found to act as a "bridge" between C5a and gammadelta T cells in a mechanism involving IL-6 and transforming growth factor beta (TGF-beta). These results imply that C5a affects the crosstalk between DC and gammadelta T cells during sepsis development, and this may result in a large production of inflammatory mediators such as IL-17.

108: Journal of immunology (Baltimore, Md. : 1950), 2010 Feb 5, 133(2-4)
IL-17 Activates the Canonical NF-{kappa}B Signaling Pathway in Autoimmune B Cells of BXD2 Mice To Upregulate the Expression of Regulators of G-Protein Signaling 16.

[Abstract]We previously identified that autoreactive B cells from BXD2 mice can be targeted by IL-17, leading to upregulation of the expression of regulators of G-protein signaling (Rgs) genes that facilitated the development of spontaneous germinal centers. Little is known about the signaling pathway used by IL-17 to upregulate RGS. In the current study, we found that IL-17 rapidly activates the canonical NF-kappaB signaling pathway and that BXD2 B cells exhibit higher basal and activated phosphorylated p65 levels than B6 or BXD2-Il17ra(-/-) B cells. Inhibition of p65 phosphorylation downregulated RGS16 expression and abrogated the IL-17-induced chemotactic arrest of B cells in response to CXCL12. Knockdown of TNFR-associated factor 6 or NF-kappaB activator 1 in 70Z/3 pre-B cells led to decreased Rgs16 expression, indicating that both of these two genes are involved in IL-17-mediated activation of NF-kappaB signaling in B cells. These findings identify the signaling pathway regulated by IL-17 to contribute to the development of spontaneous germinal centers in autoimmune BXD2 mice.

109: Arthritis and rheumatism, 2010 Apr, 62(4)
LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study.

[Abstract]OBJECTIVE: We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti-interleukin-17 (anti-IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs). METHODS: This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10. RESULTS: Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821-combined groups (-2.3, -2.4, and -2.3, respectively) than in the placebo group (-1.7) at week 10 (P < or = 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events. CONCLUSION: LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.

110: Journal of clinical immunology, 2010 Feb 4, 133(2-4)
IL-17 Contributes to the Development of Chronic Rejection in a Murine Heart Transplant Model.

[Abstract]BACKGROUND: Although interleukin-17 (IL-17) has been reported to participate in the pathogenesis of infectious, autoimmune and allergic disorders, the precise role in allograft rejection remains uncertain. This study illustrates that IL-17 contributes to the pathogenesis of chronic allograft rejection. RESULT: Utilizing a murine heterotopic heart transplant model system, IL-17-deficient recipient mice had decreased allograft inflammatory cell recruitment, decreased IL-6, MCP-1, and KC production, and reduced graft coronary artery disease (GCAD). Intragraft gamma delta (gammadelta) T cells appear to be the predominant source of IL-17 production. CONCLUSION: Therefore, IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.

111: The Journal of experimental medicine, 2010 Feb 1, 78(2)
Antibodies attack IL-17.

[Abstract]Helicobacter pylori is a human gastroduodenal pathogen that leads to active chronic inflammation characterized by T-cell responses biased toward a Th1 phenotype. It has been accepted that H. pylori infection induces a Th17 response. At mucosal sites, dendritic cells (DCs) have the capacity to induce effector T cells. Here, we evaluate the role of DCs in the H. pylori-induced interleukin-17 (IL-17) response. Immunohistochemistry and immunofluorescence were performed on human gastric mucosal biopsy samples and showed that myeloid DCs in H. pylori-infected patients colocalized with IL-23- and that IL-17-producing lymphocytes were present in H. pylori-infected antral biopsy samples. In parallel, human monocyte-derived DCs stimulated in vitro with live H. pylori cells produced significant levels of IL-23 in the absence of IL-12 release. The subsequent incubation of H. pylori-infected DCs with autologous CD4(+) T cells led to gamma interferon (IFN-gamma) and IL-17 expression. The inhibition of IL-1 and, to a lesser extent, IL-23 inhibited IL-17 production by T cells. Finally, isogenic H. pylori mutant strains not expressing major virulence factors were less effective in inducing IL-1 and IL-23 release by DCs and IL-17 release by T cells than parental strains. Altogether, we can conclude that DCs are potent inducers of IL-23/IL-17 expression following H. pylori stimulation. IL-1/IL-23 as well as H. pylori virulence factors seem to play an important role in mediating this response.

112: Journal of immunology (Baltimore, Md. : 1950), 2010 Jan 29, 148(2)
IL-17 Promotes Tumor Development through the Induction of Tumor Promoting Microenvironments at Tumor Sites and Myeloid-Derived Suppressor Cells.

[Abstract]The role of immune responses in tumor development is a central issue for tumor biology and immunology. IL-17 is an important cytokine for inflammatory and autoimmune diseases. Although IL-17-producing cells are detected in cancer patients and tumor-bearing mice, the role of IL-17 in tumor development is controversial, and mechanisms remain to be fully elucidated. In the current study, we found that the development of tumors was inhibited in IL-17R-deficient mice. A defect in IFN-gammaR increased tumor growth, whereas tumor growth was inhibited in mice that were deficient in both IL-17R and IFN-gammaR compared with wild-type animals. Further experiments showed that neutralization of IL-17 by Abs inhibited tumor growth in wild-type mice, whereas systemic administration of IL-17 promoted tumor growth. The IL-17R deficiency increased CD8 T cell infiltration, whereas it reduced the infiltration of myeloid-derived suppressor cells (MDSCs) in tumors. In contrast, administration of IL-17 inhibited CD8 T cell infiltration and increased MDSCs in tumors. Further analysis indicated that IL-17 was required for the development and tumor-promoting activity of MDSCs in tumor-bearing mice. These data demonstrate that IL-17-mediated responses promote tumor development through the induction of tumor-promoting microenvironments at tumor sites. IL-17-mediated regulation of MDSCs is a primary mechanism for its tumor-promoting effects. The study provides novel insights into the role of IL-17 in tumor development and has major implications for targeting IL-17 in treatment of tumors.

113: PloS one, 2010, 5(1)
Mast Cells Mobilize Myeloid-Derived Suppressor Cells and Treg Cells in Tumor Microenvironment via IL-17 Pathway in Murine Hepatocarcinoma Model.

[Abstract]Tumor immunosuppression is commonly braided with chronic inflammation during tumor development. However, the relationship between immunosuppression and inflammation in tumor microenvironment is still unclear. We have demonstrated that mast cells are accumulated and exacerbate the inflammation and immunosuppression in tumor microenvironment via SCF/c-kit signaling pathway. Here, we further elucidate the underlying mechanism, which involves both myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells. Our data showed that mast cells mobilized the infiltration of MDSCs to tumor and induced the production of IL-17 by MDSCs; MDSCs-derived IL-17 indirectly attracted Treg cells, enhanced their suppressor function, and induced the IL-9 production by Treg cells; in turn, IL-9 strengthened the survival and protumor effect of mast cells in tumor microenvironment. Our findings disclose a closed loop among mast cells, MDSCs and Treg cells in tumor microenvironment, which provides a new insight into the paralleled developments of inflammation and immunosuppression in tumor microenvironment. Based on these findings, we propose that targeting tumor inflammation might be a potential strategy to reverse the immunosuppression of tumor microenvironment, thus facilitating cancer immunotherapy.

114: Acta physiologica (Oxford, England), 2010 Jan 22, 184(3)
Combined effect of IL-17 and blockade of nitric oxide biosynthesis on haematopoiesis in mice.

[Abstract]Abstract Aim: The study was undertaken to extend our investigation concerning both the in vivo activity of IL-17 and the specific role of nitric oxide (NO) in IL-17-induced effects in the process of haematopoiesis. Methods: CBA mice were simultaneously treated with IL-17 and/or NO synthase (NOS) inhibitor, L-NAME, for 5 days and changes within various haematopoietic cell lineages in bone marrow, spleen and peripheral blood were analyzed. Results: Findings showed that administration of both IL-17 and L-NAME stimulated increase of all net haematopoiesis in normal mice. IL-17-enhanced myelopoiesis was characterized by stimulation of both femoral and splenic haematopoietic progenitor cells and morphologically recognizable granulocytes. Additionally, IL-17 induced alterations in frequency of erythroid progenitor cells in both bone marrow and spleen, accompanied with their mobilization to the peripheral blood. As a consequence of these changes in the erythroid cell compartments, significant reticulocytosis was observed, which evidenced that in IL-17-treated mice effective erythropoiesis occurred. Exposure of mice to NOS inhibitor also increased the number of both granulocyte-macrophage and erythroid progenitors in bone marrow and spleens, and these alterations were followed by the mobilization of erythroid progenitors and elevated content of reticulocytes in peripheral blood. The specific role of NO in IL-17-induced haematopoiesis was demonstrated only in the IL-17 reducing effect on bone marrow late stage erythroid progenitors, CFU-E. Conclusion: Results obtained demonstrated involvement of both IL-17 and NO in the regulation of haematopoietic cells activity in various haematopoietic compartments. They further suggest that IL-17 effects are differentially mediated depending on the haematopoietic microenvironments.

115: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2010 Jan 25, 184(3)
Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis.

[Abstract]BACKGROUND: The Th17 subset has been implicated in the pathogenesis of a number of autoimmune diseases. However, little is known about its role in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). We measured serum levels of IL-17A and associated upstream cytokines and the frequency of IL-17-producing autoantigen-specific T cells in patients with AAV. METHODS: ELISA on sera from acute (n = 28) and convalescent (n = 65) patients with AAV from Hammersmith Hospital was performed for IL-17A and the associated upstream cytokines IL-23, IL-6 and IL-1beta, as well as the Th1 cytokine IFN-gamma. ELISPOT was performed to measure autoantigen-specific recall T cell responses in convalescent patients and the frequency of IL-17- and IFN-gamma-producing cells. RESULTS: Serum IL-17A and IL-23 levels were significantly elevated in acute AAV patients compared to healthy controls (P < 0.01 and P < 0.001, respectively), but importantly, remained elevated in a proportion of convalescent patients. By contrast, no significant differences in IFN-gamma levels were detected between patient groups and controls. Patients with elevated levels of IL-23 compared to those with low IL-23 had more active disease as measured by Birmingham Vasculitis Activity Score (P < 0.05) and had higher ANCA titres (P < 0.05). Critically, immunosuppressive therapy did not always effectively suppress IL-23 or IL-17 production. Additionally, autoantigen-specific IL-17-producing, but not IFN-gamma-producing, cells were significantly elevated in patients during disease convalescence compared to healthy controls. CONCLUSIONS: These data implicate the Th17 axis and specifically IL-23 as mediators of more severe disease in AAV. Their persistence despite conventional treatment may contribute to high relapse rates.

116: Journal of immunology (Baltimore, Md. : 1950), 2010 Jan 18, 184(3)
IL-23 Receptor Regulates Unconventional IL-17-Producing T Cells That Control Bacterial Infections.

[Abstract]IL-23 plays an important role in autoimmune tissue inflammation and induces the generation of not fully characterized effector cells that mediate protection against pathogens. In this paper, we established the essential role of IL-23R in the host response against intracellular pathogens. IL-23 was critical for the expansion or maintenance of gammadelta and double negative (DN) alphabeta T cells. These cells were rapidly recruited to the site of infection and produced large amounts of IL-17, IFN-gamma, and TNF-alpha. Notably, DN T cells transferred into L. monocytogenes-infected RAG2(-/-) mice prevented bacterial growth, confirming their protective role against intracellular pathogens. Our results show that IL-23 regulates the function of IL-17-producing gammadelta and DN T cells, two essential components of the early protective immune response directed against intracellular pathogens.

117: Molecular immunology, 2010 Jan 15, 184(2)
Regulation of IL-17 expression by the developmental pathway of CD4 T cells in the thymus.

[Abstract]CD4 T cells selected by MHC class II expressing thymocytes (T-CD4 T cells) have distinct effector functions compared to that of epithelial cell-selected CD4 T cells (E-CD4 T cells). T-CD4 T cells produce both Th1 and Th2 effector cytokines immediately after stimulation and also express IL-4 in addition to IFN-gamma under the Th1 differentiation condition. In the present study, we investigated the capability of T-CD4 T cells to become IL-17-producing cells. We found that T-CD4 T cells express reduced IL-17 under Th17-inducing conditions. T-CD4 T cells express very low levels of receptor for TGF-beta and IL-21 that are essential to induce IL-17 expression. In addition, the induction of RORgammat, a key transcription factor for IL-17 gene expression, was compromised in T-CD4 T cells under Th17 skewing conditions and ectopic expression of RORgammat restored IL-17 expression. The defect of IL-17 and RORgammat expression in T-CD4 T cells is cell intrinsic and not due to effects of a secreted factor. Thus, the developmental pathway of CD4 T cells in the thymus plays a critical role in controlling an immune response by suppressing the generation of the Th17 lineage.

118: Journal of immunology (Baltimore, Md. : 1950), 2010 Jan 8, 184(2)
Cutting Edge: Spontaneous Development of IL-17-Producing {gamma}{delta} T Cells in the Thymus Occurs via a TGF-{beta}1-Dependent Mechanism.

[Abstract]In naive animals, gammadelta T cells are innate sources of IL-17, a potent proinflammatory cytokine mediating bacterial clearance as well as autoimmunity. However, mechanisms underlying the generation of these cells in vivo remain unclear. In this study, we show that TGF-beta1 plays a key role in the generation of IL-17(+) gammadelta T cells and that it mainly occurs in the thymus particularly during the postnatal period. Interestingly, IL-17(+) gammadelta TCR(+) thymocytes were mainly CD44(high)CD25(low) cells, which seem to derive from double-negative 4 gammadelta TCR(+) cells that acquired CD44 and IL-17 expression. Our findings identify a novel developmental pathway during which IL-17-competent gammadelta T cells arise in the thymus by a TGF-beta1-dependent mechanism.

119: Journal of immunology (Baltimore, Md. : 1950), 2009 Dec 30, 78(1)
IL-17 Regulates CXCL1 mRNA Stability via an AUUUA/Tristetraprolin-Independent Sequence.

[Abstract]IL-17 contributes to inflammatory response in part by promoting enhanced expression of chemokines, such as CXCL1, by prolonging the t(1/2) of this constitutively unstable mRNA. Although IL-17 is a weak stimulus for transcription of the CXCL1 gene, it strongly potentiates message accumulation via stabilization when the mRNA is transcribed in cells stimulated with TNF. In myeloid cells, LPS-induced CXCL1 mRNA stabilization is dependent on AUUUA-containing sequence motifs that are recognized by the RNA binding protein tristetraprolin (TTP). Using deletion and site-specific mutagenesis, we report that IL-17-mediated stabilization of CXCL1 mRNA in nonmyeloid cells depends on a sequence that does not contain the AUUUA motif. Furthermore, a specific two-nucleotide mutation within this region markedly abrogates sensitivity for IL-17-mediated stabilization. Consistent with this finding, the IL-17-sensitive sequence does not exhibit increased instability in the presence of TTP, and CXCL1 mRNA remains unstable and can be stabilized in response to treatment with IL-17 in embryo fibroblasts from mice in which the TTP gene has been deleted. Whereas the RNA binding protein KSRP has been shown to participate in regulating the instability of human CXCL8 mRNA, inhibitory RNA-based reduction in KSRP does not effect the instability mediated by the IL-17-sensitive sequence motif. These findings suggest that IL-17-mediated chemokine mRNA stabilization in nonmyeloid cells uses a mechanism that is distinct from that operating to control AU-rich mRNA stability in myeloid cells.

120: The Journal of clinical investigation, 2009 Dec 14, 132(2-4)
IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury.

[Abstract]The IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways have a role in chronic autoimmunity, which is considered mainly a dysfunction of adaptive immunity. The extent to which they contribute to innate immunity is, however, unknown. We used a mouse model of acute kidney ischemia-reperfusion injury (IRI) to test the hypothesis that early production of IL-23 and IL-12 following IRI activates downstream IL-17 and IFN-gamma signaling pathways and promotes kidney inflammation. Deficiency in IL-23, IL-17A, or IL-17 receptor (IL-17R) and mAb neutralization of CXCR2, the p19 subunit of IL-23, or IL-17A attenuated neutrophil infiltration in acute kidney IRI in mice. We further demonstrate that IL-17A produced by GR-1+ neutrophils was critical for kidney IRI in mice. Activation of the IL-12/IFN-gamma pathway and NKT cells by administering alpha-galactosylceramide-primed bone marrow-derived DCs increased IFN-gamma production following moderate IRI in WT mice but did not exacerbate injury or enhance IFN-gamma production in either Il17a-/- or Il17r-/- mice, which suggested that IL-17 signaling was proximal to IFN-gamma signaling. This was confirmed by the finding that IFN-gamma administration reversed the protection seen in Il17a-/- mice subjected to IRI, whereas IL-17A failed to reverse protection in Ifng-/- mice. These results demonstrate that the innate immune component of kidney IRI requires dual activation of the IL-12/IFN-gamma and IL-23/IL-17 signaling pathways and that neutrophil production of IL-17A is upstream of IL-12/IFN-gamma. These mechanisms might contribute to reperfusion injury in other organs.

121: Hypertension, 2009 Dec 28, 78(1)
Interleukin 17 Promotes Angiotensin II-Induced Hypertension and Vascular Dysfunction.

[Abstract]We have shown previously that T cells are required for the full development of angiotensin II-induced hypertension. However, the specific subsets of T cells that are important in this process are unknown. T helper 17 cells represent a novel subset that produces the proinflammatory cytokine interleukin 17 (IL-17). We found that angiotensin II infusion increased IL-17 production from T cells and IL-17 protein in the aortic media. To determine the effect of IL-17 on blood pressure and vascular function, we studied IL-17(-/-) mice. The initial hypertensive response to angiotensin II infusion was similar in IL-17(-/-) and C57BL/6J mice. However, hypertension was not sustained in IL-17(-/-) mice, reaching levels 30-mm Hg lower than in wild-type mice by 4 weeks of angiotensin II infusion. Vessels from IL-17(-/-) mice displayed preserved vascular function, decreased superoxide production, and reduced T-cell infiltration in response to angiotensin II. Gene array analysis of cultured human aortic smooth muscle cells revealed that IL-17, in conjunction with tumor necrosis factor-alpha, modulated expression of >30 genes, including a number of inflammatory cytokines/chemokines. Examination of IL-17 in diabetic humans showed that serum levels of this cytokine were significantly increased in those with hypertension compared with normotensive subjects. We conclude that IL-17 is critical for the maintenance of angiotensin II-induced hypertension and vascular dysfunction and might be a therapeutic target for this widespread disease.

122: Transplant immunology, 2009 Dec 23, 78(1)
Splenic autotransplantation restores IL-17 production and antibody response to Streptococcus pneumoniae in splenectomized mice.

[Abstract]The high incidence of overwhelming postsplenectomy infection caused by Streptococcus pneumoniae can be reduced by splenic autotransplantation. In this study the effect of splenectomy and splenic autotransplantation on the immune response to S. pneumoniae infection was investigated. Balb/c mice were divided into three groups: splenectomized (SP), splenectomized and autotransplanted (AT), and sham operated control (CT). Five days post-infection the serum antibody levels were measured and the number of S. pneumoniae CFU, neutrophil accumulation and IL-17 production in the liver and lungs were investigated. SP mice showed greater number of bacteria in both organs and lower serum levels of S. pneumoniae-specific IgM, IgG1 and IgG2a antibodies. IL-17 production and neutrophil recruitment to the liver and lungs were lower in SP mice, in comparison with both the CT and the AT groups. Levels of S. pneumoniae-specific IgM, CFU counts, neutrophil accumulation and IL-17 production did not differ significantly between the CT and AT groups. These results suggest that splenic autotransplantation restores the capacity of splenectomized mice to fight S. pneumoniae infection.

123: Journal of immunology (Baltimore, Md. : 1950), 2009 Dec 18, 206(13)
IFN-{gamma} Regulates the Requirement for IL-17 in Proteoglycan-Induced Arthritis.

[Abstract]The contribution of the proinflammatory cytokines IFN-gamma and IL-17 to the pathogenesis of experimental arthritis is controversial. In proteoglycan (PG)-induced arthritis (PGIA), severe arthritis is dependent on the production of IFN-gamma, whereas IL-17 is dispensable. In collagen-induced arthritis and Ag-induced arthritis, although high levels of IFN-gamma are secreted, disease is exacerbated in IFN-gamma or IFN-gamma receptor-deficient mice due to the ability of IFN-gamma to suppress IL-17 expression. In the current study, we investigated the effect of IFN-gamma on the IL-17 response and its consequences in PGIA. In PG-immunized IFN-gamma(-/-) mice, despite reduction in arthritis, the PG-specific CD4(+) T cell IL-17 response was significantly increased. Elevated IL-17 contributed to development of arthritis, as disease in IFN-gamma/IL-17(-/-) was significantly reduced in comparison with either IFN-gamma(-/-) or IL-17(-/-) mice. A contribution of IFN-gamma and IL-17 to the development of arthritis was also identified in T-bet(-/-) mice. PG-specific CD4(+) T cells from T-bet(-/-) mice produced reduced IFN-gamma and elevated concentrations of IL-17. Both IFN-gamma and IL-17 contribute to arthritis, as T-bet(-/-) mice lacking IL-17 (T-bet/IL-17(-/-)) were resistant, whereas wild-type, T-bet(-/-), and IL-17(-/-) mice were susceptible to PGIA. T cell proliferation and autoantibody production did not correlate with development of disease; however, expression of cytokines and chemokines in joint tissues demonstrate that IFN-gamma and IL-17 cooperatively contribute to inflammation. These results demonstrate that both IFN-gamma and IL-17 have the potential to induce PGIA, but it is the strength of the IFN-gamma response that regulates the contribution of each of these Th effector cytokines to disease.

124: Lung cancer (Amsterdam, Netherlands), 2009 Dec 16, 206(13)
Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients.

[Abstract]The presence of IL-17-positive cells is observed in a variety of inflammatory associated cancers and IL-17 has been found to be involved in angiogenesis. The aim of this study is to determine the prognostic significance of IL-17 in NSCLC patients and to examine the correlation between IL-17 expression and lymphatic vessel density in NSCLC tissues. The expression of IL-17 was measured by immunohistochemistry in 52 paraffin-embedded tissues with non-small cell lung cancer. The chi(2) test was used to analyze the correlation between IL-17 expression and clinical parameters and lymphatic vessel density (LVD). The Kaplan-Meier method, univariate and multivariate regression analysis was used to analyze the correlation between IL-17 expression and overall survival and disease-free survival. High expression of IL-17 was observed in 25 of 52 lung cancer patients and was associated with smoking status, TNM stage, LVD, overall survival and disease-free survival. Univariate and multivariate analysis showed that IL-17 was an independent prognostic factor for overall survival and disease-free survival. Our results indicate that IL-17 may play a role in the metastasis of lung cancer by promoting lymphangiogenesis. IL-17 expression is an independent prognostic factor in both overall and disease-free survival in NSCLC.

125: Journal of immunology (Baltimore, Md. : 1950), 2009 Dec 16, 11(1)
AIDS Progression Is Associated with the Emergence of IL-17-Producing Cells Early After Simian Immunodeficiency Virus Infection.

[Abstract]IL-17 is a potent effector cytokine involved in inflammatory response and antimicrobial defense. We report that SIV infection of rhesus macaques (RMs) results in the emergence of IL-17-expressing cells during the acute phase. This subpopulation appears at day 14 postinfection concomitantly with an increase in TGF-beta and IL-18 expression. This subset, which exhibits phenotypic markers of NK T cells (NKT), rather than Th17 CD4 cells, persists during the chronic phase and is higher in noncontrollers SIV-infected RMs compared with controllers SIV-infected RMs. In contrast, in the nonpathogenic model of SIVagm infection of African green monkeys, no change in the level of IL-17-expressing cells is observed in lymphoid organs. Consistent with the emergence of TGF-beta and IL-18 during the acute phase in SIV-infected RMs, but not in SIV-infected African green monkeys, we demonstrate that in vitro TGF-beta and IL-18 induce the differentiation and expansion of IL-17(+)NKT(+). Altogether, these results demonstrate that IL-17-producing NKT are associated with the pathogenesis of SIV in RMs and suggest that TGF-beta and IL-18 play a role in their development.

126: Nature immunology, 2010 Jan, 11(1)
Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation.

[Abstract]

127: Clinical immunology (Orlando, Fla.), 2009 Dec 14, 132(2-4)
Suppressive influences of IFN-alpha on IL-17 expression in human CD4+ T cells.

[Abstract]We examined the direct effects of IFN-alpha on the development of Th17 with a system using immobilized anti-CD3, which permits activation of CD4+ T cells in the complete absence of accessory cells. Highly purified CD4+ T cells obtained from healthy donors were stimulated with immobilized anti-CD3 with or without IFN-alpha. IFN-alpha suppressed the production of IL-17 of immobilized anti-CD3-stimulated CD4+ T cells in a dose-response manner. Accordingly, IFN-alpha inhibited IL-17 mRNA expression in immobilized anti-CD3-stimulated CD4+ T cells. IFN-alpha did not affect the production of TGF-beta or IL-6, but inhibited RORC mRNA expression of anti-CD3-stimulated CD4+ T cells. These results indicate that IFN-alpha suppresses IL-17 expression and Th17 differentiation through down-regulation of RORC mRNA expression. It is therefore suggested that these effects might play a role in the mode of action of IFN-alpha in the treatment of various inflammatory diseases.

128: Seminars in immunopathology, 2009 Dec 13, 132(2-4)
IL-17RC: a partner in IL-17 signaling and beyond.

[Abstract]The interleukin (IL)-17 cytokine family members IL-17A and IL-17F mediate inflammatory activities via the IL-17 receptor (IL-17R) complex, comprised of the IL-17RA and IL-17RC subunits. Proper regulation of the IL-17 signaling axis results in effective host defense against extracellular pathogens, while aberrant signaling can drive autoimmune pathology. Elucidating the molecular mechanisms underlying IL-17 signal transduction can yield an enhanced understanding of inflammatory immune processes and also create an avenue for therapeutic intervention in the treatment of IL-17-dependent diseases. To date, the fundamental signaling mechanisms used by the IL-17R complex are still incompletely defined. While current structure-function studies have primarily focused on the IL-17RA subunit, recent research indicates that the IL-17RC subunit plays a key role in modulating IL-17 responses. This review will examine what is known regarding IL-17RC function and provide a framework for future work on this subunit and its impact on human health.

129: Infection and immunity, 2009 Dec 7, 132(2-4)
Morphine Disrupts the IL-23/IL-17 Mediated Pulmonary Mucosal Host Defense Against S. pneumoniae Infection.

[Abstract]S. pneumoniae is a pathogen that causes serious respiratory disease and meningitis in the immunocompromised drug abuse population. However, the precise mechanisms by which drug abuse compromises the host immune defense to pulmonary S. pneumoniae infection is not fully understood. Using a well-established murine model of opiate abuse and S. pneumoniae lung infection, we explored the influence of morphine treatment on the IL-23/IL-17 axis and related innate immunity. Impairment of early IL-23/IL-17 production caused by morphine treatment was associated with delayed neutrophil migration and decreased pneumococcal clearance. Furthermore, morphine treatment impaired MyD88 dependent IL-23 production in alveolar macrophages and dendritic cells in response to in vitro S. pneumoniae cell infection. Moreover, morphine treatment significantly inhibited the S. pneumoniae induced phosphorylation of IRF3, ATF2, and NF-kappaBp65. TCRdelta deficient mice showed a decrease in IL-17 production and a severely weakened capacity to clear lung S. pneumoniae infection. Finally, morphine treatment resulted in diminished secretion of antimicrobial proteins S100A9 and S100A8/A9 during early stages of S. pneumoniae infection. In conclusion, morphine treatment causes a dysfunction in IL-23-producing dendritic cells and macrophages, and IL-17- producing gammadeltaT lymphocytes in response to S. pneumoniae lung infection. This leads to diminished release of anti-microbial proteins S100A8/A9 proteins, compromised neutrophil recruitment, and more severe infection.

130: Pain, 2009 Dec 5, 132(2-4)
IL-17 mediates articular hypernociception in antigen-induced arthritis in mice.

[Abstract]IL-17 is an important cytokine in the physiopathology of rheumatoid arthritis (RA). However, its participation in the genesis of nociception during RA remains undetermined. In this study, we evaluated the role of IL-17 in the genesis of articular nociception in a model of antigen (mBSA)-induced arthritis. We found that mBSA challenge in the femur-tibial joint of immunized mice induced a dose- and time-dependent mechanical hypernociception. The local IL-17 concentration within the mBSA-injected joints increased significantly over time. Moreover, co-treatment of mBSA challenged mice with an antibody against IL-17 inhibited hypernociception and neutrophil recruitment. In agreement, intraarticular injection of IL-17 induced hypernociception and neutrophil migration, which were reduced by the pre-treatment with fucoidin, a leukocyte adhesion inhibitor. The hypernociceptive effect of IL-17 was also reduced in TNFR1(-/-) mice and by pre-treatment with infliximab (anti-TNF antibody), a CXCR1/2 antagonist or by an IL-1 receptor antagonist. Consistent with these findings, we found that IL-17 injection into joints increased the production of TNF-alpha, IL-1beta and CXCL1/KC. Treatment with doxycycline (non-specific MMPs inhibitor), bosentan (ET(A)/ET(B) antagonist), indomethacin (COX inhibitor) or guanethidine (sympathetic blocker) inhibited IL-17-induced hypernociception. IL-17 injection also increased PGE(2) production, MMP-9 activity and COX-2, MMP-9 and PPET-1 mRNA expression in synovial membrane. These results suggest that IL-17 is a novel pro-nociceptive cytokine in mBSA-induced arthritis, whose effect depends on both neutrophil migration and various pro-inflammatory mediators, as TNF-alpha, IL-1beta, CXCR1/2 chemokines ligands, MMPs, endothelins, prostaglandins and sympathetic amines. Therefore, it is reasonable to propose IL-17 targeting therapies to control this important RA symptom.

131: Journal of reproductive immunology, 2009 Dec 5, 132(2-4)
A role for IL-17 in induction of an inflammation at the fetomaternal interface in preterm labour.

[Abstract]Chorioamnionitis (CAM) is a major cause of preterm delivery. Inflammatory cytokines and chemokines play important roles in the pathogenesis of preterm delivery. Interleukin (IL)-17 is a key cytokine which induces inflammation and is critical to host defense. In this study, we examined the role of IL-17 in the pathogenesis of preterm delivery. The levels of cytokines including IL-17, IL-8 and tumor necrosis factor (TNF) alpha were measured by ELISA in amniotic fluid from 154 cases of preterm labor. Flow cytometry and immunohistochemical staining were performed to determine the distribution of IL-17-producing cells. IL-8 secretion was evaluated in primary cultured human amniotic mesenchymal (HAM) cells and human amniotic epithelial (HAE) cells stimulated with IL-17, TNFalpha or IL-1beta. We also studied the signaling pathway of IL-17 and TNFalpha in HAM cells. Levels of inflammatory cytokines in amniotic fluid were higher in preterm delivery cases than in term delivery cases. Furthermore, IL-8, IL-17 and TNFalpha levels were significantly higher in the preterm cases with CAM stage II or III than those without CAM. Flow cytometry and immunohistochemical staining revealed that CD3(+)CD4(+) T cells were the main source of IL-17 in the chorioamniotic membrane. Interestingly, TNFalpha-induced IL-8 secretion was enhanced by IL-17 in a dose-dependent manner in HAM cells. The IKK inhibitor BMS-345541 and mitogen-activated protein kinase (MAPK) inhibitors p38, JNK and p42/44 (ERK1/2 pathway) reduced IL-8 secretion by IL-17-stimulated and TNFalpha-stimulated HAM cells. These results indicate that IL-17, produced by T cells, promotes inflammation at the fetomaternal interface in preterm delivery.

132: Proceedings of the National Academy of Sciences of the United States of America, 2009 Dec 2, 127(1)
IL-17-producing T cells can augment autoantibody-induced arthritis.

[Abstract]Rheumatoid arthritis is a T lymphocyte-mediated disorder, but the precise nature of T cell involvement remains unclear. In the K/BxN mouse model of inflammatory arthritis, T cells initiate disease by providing help to B cells to produce arthritogenic autoantibodies. Here, we have characterized an additional, nonhumoral role for T cells in promoting autoantibody-induced arthritis. Autoreactive KRN T cells introduced either by direct transfer or bone marrow transplantation into B-cell-deficient hosts enhanced K/BxN serum-transferred arthritis, an effect that was dependent on expression of the cognate MHC-molecule/peptide complex. The T cell influence was dependent on interleukin (IL)-17; in contrast, standard serum-transferred arthritis, unenhanced by the addition of T cells, was unaffected by IL-17 neutralization. An IL-17-producing population of transferred KRN T cells was identified and found to be supported by the cotransfer of arthritogenic autoantibodies. IL-17-producing KRN T cells were enriched in inflamed joints of K/BxN mice, suggesting either selective recruitment or preferential differentiation. These results demonstrate the potential for autoreactive T cells to play two roles in the development of arthritis, both driving the production of pathogenic autoantibodies and bolstering the subsequent inflammatory cascade dependent on the innate immune system.

133: International archives of allergy and immunology, 2009 Nov 24, 152(1)
Differential Mucosal IL-17 Expression in Two Gliadin-Induced Disorders: Gluten Sensitivity and the Autoimmune Enteropathy Celiac Disease.

[Abstract]Background: The immune-mediated enteropathy, celiac disease (CD), and gluten sensitivity (GS) are two distinct clinical conditions that are both triggered by the ingestion of wheat gliadin. CD, but not GS, is associated with and possibly mediated by an autoimmune process. Recent studies show that gliadin may induce the activation of IL-17-producing T cells and that IL-17 expression in the CD mucosa correlates with gluten intake. Methods: The small-intestinal mucosa of patients with CD and GS and dyspeptic controls was analyzed for expression of IL-17A mRNA by quantitative RT-PCR. The number of CD3+ and TCR-gammadelta lymphocytes and the proportion of CD3+ cells coexpressing the Th17 marker CCR6 were examined by in situ small-intestinal immunohistochemistry. Results: Mucosal expression of IL-17A was significantly increased in CD but not in GS patients, compared to controls. This difference was due to enhanced IL-17A levels in >50% of CD patients, with the remainder expressing levels similar to GS patients or controls, and was paralleled by a trend toward increased proportions of CD3+CCR6+ cells in intestinal mucosal specimens from these subjects. Conclusion: We conclude that GS, albeit gluten-induced, is different from CD not only with respect to the genetic makeup and clinical and functional parameters, but also with respect to the nature of the immune response. Our findings also suggest that two subgroups of CD, IL-17-dependent and IL-17-independent, may be identified based on differential mucosal expression of this cytokine.

134: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2009 Nov 25, 216(1-2)
Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

[Abstract]Recently T-helper 17 (Th17) cells were demonstrated to disrupt the blood-brain barrier (BBB) by the action of IL-17A. The aim of the present study was to examine the mechanisms that underlie IL-17A-induced BBB breakdown. Barrier integrity was analyzed in the murine brain endothelial cell line bEnd.3 by measuring the electrical resistance values using electrical call impedance sensing technology. Furthermore, in-cell Western blots, fluorescence imaging, and monocyte adhesion and transendothelial migration assays were performed. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. IL-17A induced NADPH oxidase- or xanthine oxidase-dependent reactive oxygen species (ROS) production. The resulting oxidative stress activated the endothelial contractile machinery, which was accompanied by a down-regulation of the tight junction molecule occludin. Blocking either ROS formation or myosin light chain phosphorylation or applying IL-17A-neutralizing antibodies prevented IL-17A-induced BBB disruption. Treatment of mice with EAE using ML-7, an inhibitor of the myosin light chain kinase, resulted in less BBB disruption at the spinal cord and less infiltration of lymphocytes via the BBB and subsequently reduced the clinical characteristics of EAE. These observations indicate that IL-17A accounts for a crucial step in the development of EAE by impairing the integrity of the BBB, involving augmented production of ROS.-Huppert, J., Closhen, D., Croxford, A., White, R., Kulig, P., Pietrowski, E., Bechmann, I., Becher, B., Luhmann, H. J., Waisman, A., Kuhlmann, C. R. W. Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

135: International immunopharmacology, 2009 Nov 19, 6(5)
Neutralization of IL-17 inhibits the production of anti-ANT autoantibodies in CVB3-induced acute viral myocarditis.

[Abstract]Anti-adenine nucleotide translocator (ANT) autoantibodies are related to the development of Coxsackievirus B3 (CVB3)-triggered acute viral myocarditis (AVMC). Recently, studies suggested that IL-17 especially produced by a novel CD4(+) Th-cell subset Th17 cells contributed to the production of pathogenic autoantibodies in some autoimmune diseases. However, the pathogenic role of IL-17 in AVMC remains largely unknown. In this study, we investigated whether IL-17 was associated with the disease progression and the production of anti-ANT autoantibodies in AVMC mouse model. The results showed that IL-17 monoclonal antibody (mAb)-treated AVMC mice had decreased HW/BW, reduced serum CK-MB activity and improved pathological score of heart sections along with the reduction of circulating IL-17 level and serum anti-ANT autoantibodies. The correlation index of serum IL-17 concentration and anti-ANT-autoantibody level was 0.874, p<0.01. In addition, the experimental results in vitro further proved that IL-17mAb could inhibit the proliferation of CD19(+) B lymphocytes and the secretion of anti-ANT autoantibodies. Our data suggested that IL-17 was related to the disease progression in AVMC mouse model by regulating the production of autoantibodies and blocking IL-17 might represent a promising novel therapeutic approach.

136: Immunity, 2009 Nov 20, 31(5)
Interleukin-17 kick-starts T helper 1 cell differentiation.

[Abstract]In this issue of Immunity, Lin et al. (2009) implicate interleukin-17 in the regulation of T helper 1 (Th1) cell immunity against Francisella tularensis. These findings add a unique twist to the cytokine regulation of T cell differentiation and function.

137: Biochemical and biophysical research communications, 2009 Nov 19, 31(5)
IL-17 primes airway epithelial cells lacking functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) to increase NOD1 responses.

[Abstract]In Cystic Fibrosis (CF), the absence of functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) translates into chronic bacterial infection, excessive inflammation, tissue damage, impaired lung function and eventual death. Understanding the mechanisms underlying this vicious circle of inflammation is key to better therapies for CF. In this manuscript, we have found that the presence of IL-17 in the airways of CF patients not only exacerbates inflammation through the recruitment of neutrophils via secretion of CXCL8, but also by priming airway epithelial cells lacking functional CFTR to increase response to the bacterial sensor NOD1. IL-17 stimulation of airway epithelial cells (AECs) lacking functional CFTR increased the expression of NOD1, NOD2, TLR4 and its own receptors IL-17RA and IL-17RC. Moreover, prior stimulation of AECs expressing the CFTRDeltaF508 mutant with IL-17 showed much greater CXCL8 secretion in response to a NOD1 agonist and Pseudomonas aeruginosa diffusible material. Taken together our results show that IL-17 primes AECs expressing CFTRDeltaF508 to increase host defence response to bacteria through the up-regulation of PRRs, and in particular of NOD1, and identifies another mechanism of action through which the CFTRDeltaF508 mutation leads to increase inflammation in response to bacterial ligands. Therefore preventing IL-17 function in CF may prove an important strategy in decreasing lung inflammation due to both direct and indirect effects.

138: Infection and immunity, 2009 Nov 16, 6(5)
Helicobacter pylori Stimulates Dendritic Cells to Induce IL-17 Expression From CD4+ T lymphocytes.

[Abstract]Helicobacter pylori is a human gastroduodenal pathogen that leads to active chronic inflammation characterised by T cell responses biased towards a Th1 phenotype. It has been accepted that H. pylori infection induces a Th17 response. At mucosal sites, dendritic cells (DCs) have the capacity to induce effector T cells. Here, we evaluate the role of DCs in the H. pylori-induced IL-17 response. Immunohistochemistry and immunofluorescence were performed on human gastric mucosal biopsy samples and showed that myeloid DCs in H. pylori infected patients colocalised with IL-23 and that IL-17 producing lymphocytes were present in H. pylori infected antral biopsy samples. In parallel, human monocyte-derived DCs stimulated in vitro with live H. pylori produced significant levels of IL-23 in the absence of IL-12 release. Subsequent incubation of H. pylori infected DCs with autologous CD4(+) T cells led to IFN-gamma and IL-17 expression. Inhibition of IL-1 and, to a lesser extent, IL-23 inhibited IL-17 production by T cells. Finally, isogenic H. pylori mutant strains not expressing major virulence factors were less effective in inducing IL-1 and IL-23 release by DCs and IL-17 by T cells compared to parental strains. Altogether we can conclude that DCs are potent inducers of IL-23/IL-17 expression following H. pylori stimulation. IL-1/IL-23 as well as H. pylori virulence factors seem to play an important role in mediating this response.

139: Journal of immunology (Baltimore, Md. : 1950), 2009 Nov 16, 6(5)
Role of T Cell TGF{beta} Signaling and IL-17 in Allograft Acceptance and Fibrosis Associated with Chronic Rejection.

[Abstract]Chronic allograft rejection (CR) is the main barrier to long-term transplant survival. CR is a progressive disease defined by interstitial fibrosis, vascular neointimal development, and graft dysfunction. The underlying mechanisms responsible for CR remain poorly defined. TGFbeta has been implicated in promoting fibrotic diseases including CR, but is beneficial in the transplant setting due to its immunosuppressive activity. To assess the requirement for T cell TGFbeta signaling in allograft acceptance and the progression of CR, we used mice with abrogated T cell TGFbeta signaling as allograft recipients. We compared responses from recipients that were transiently depleted of CD4(+) cells (that develop CR and express intragraft TGFbeta) with responses from mice that received anti-CD40L mAb therapy (that do not develop CR and do not express intragraft TGFbeta). Allograft acceptance and suppression of graft-reactive T and B cells were independent of T cell TGFbeta signaling in mice treated with anti-CD40L mAb. In recipients transiently depleted of CD4(+) T cells, T cell TGFbeta signaling was required for the development of fibrosis associated with CR, long-term graft acceptance, and suppression of graft-reactive T and B cell responses. Furthermore, IL-17 was identified as a critical element in TGFbeta-driven allograft fibrosis. Thus, IL-17 may provide a therapeutic target for preventing graft fibrosis, a measure of CR, while sparing the immunosuppressive activity of TGFbeta.

140: Cell host & microbe, 2009 Nov 19, 6(5)
Aging Promotes Neutrophil-Induced Mortality by Augmenting IL-17 Production during Viral Infection.

[Abstract]Morbidity and mortality associated with viral infections increase with age, although the underlying mechanisms are unclear. Here, we investigated whether aging alters inflammatory responses during systemic viral infection and thereby contributes to virus-induced death. We found that infection of aged mice with systemic herpes viruses led to rapid increases in serum IL-17, neutrophil activation, and mortality due to hepatocyte necrosis. In contrast, all young mice survived infection, displaying weaker IL-17 induction and neutrophil activation. Natural killer T (NKT) cells isolated from the livers of aged mice produced more IL-17 than did young cells, and adoptively transferred aged NKT cells induced liver injury in young mice impaired in viral control. Importantly, IL-17 neutralization or neutrophil depletion during viral infection reduced liver damage and prevented death of aged mice. These results demonstrate that, during systemic viral infection, aging alters the host-pathogen interaction to overproduce IL-17, contributing to liver injury and death.

141: Journal of immunology (Baltimore, Md. : 1950), 2009 Nov 13, 10(12)
Systemic Increase in the Ratio between Foxp3+ and IL-17-Producing CD4+ T Cells in Healthy Pregnancy but Not in Preeclampsia.

[Abstract]Preeclampsia is the leading cause of morbidity and mortality in pregnancy. Although the etiology of preeclampsia is still unclear, it is believed to involve rejection of the fetus, possibly due to an imbalance between regulatory (Treg) and effector T cells. To test this, we compared the frequencies of circulating CD4(+) T cells expressing Foxp3, IFN-gamma, IL-10, or IL-17 at the end of the third trimester of healthy and preeclamptic pregnancies. The size of the Treg cell compartment, defined by the frequency of CD4(+)CD25(high), CD4(+)CD127(low)CD25(+), and CD4(+)Foxp3(+) cells was significantly higher in normal compared with preeclamptic pregnancies. CD4(+)CD25(high) and CD4(+)CD127(low)CD25(+) populations in preeclampsia were not significantly different from those in nonpregnant controls, whereas CD4(+)Foxp3(+) cells numbersre slightly lower in preeclampsia. The suppressive activity of ex vivo-sorted CD4(+)CD127(low)CD25(+) Treg cells was not significantly different between the three study groups. The percentage of CD4(+)IL-17-producing T cells decreased significantly in healthy compared with preeclamptic pregnancies and nonpregnant controls, whereas CD4(+)IL-10- and CD4(+)IFN-gamma-producing cells remained unchanged. Consequently, the ratio of Foxp3(+) Treg to IL-17-expressing CD4(+) T cells was significantly increased in healthy but not in preeclamptic pregnancies. Thus, preeclampsia is associated with the absence of normal systemic skewing away from IL-17 production toward Foxp3(+) expression. Finally, preeclamptic women had significantly higher levels of soluble endoglin, an inhibitor of TGF-beta receptor signaling, which may bias toward IL-17 production. These results suggest that homeostasis between regulatory and proinflammatory CD4(+) T cells might be pivotal for the semiallogeneic fetus to be tolerated within the maternal environment.

142: Clinical and experimental immunology, 2009 Nov 11, 10(12)
Translational Mini-Review Series on Th17 Cells: Induction of interleukin-17 production by regulatory T cells.

[Abstract]Summary Uncommitted (naive) CD4(+) T helper cells (Thp) can be induced to differentiate to specific lineages according to the local cytokine milieu, towards T helper type 1 (Th1), Th2, Th17 and regulatory T cell (T(reg)) phenotypes in a mutually exclusive manner. Each phenotype is characterized by unique signalling pathways and expression of specific transcription factors, notably T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for T(regs) and receptor-related orphan receptor (ROR)alpha and RORgammat for Th17 cells. T(regs) and Th17 cells have been demonstrated to arise from common precursors in a reciprocal manner based on exposure to transforming growth factor (TGF)-beta or TGF-beta plus interleukin (IL)-6 and carry out diametrically opposing functions, namely suppression or propagation of inflammation, respectively. However, while epigenetic modifications in Th1 and Th2 differentiated cells prevents their conversion to other phenotypes, Th17 cells generated in vitro using TGF-beta and IL-6 are unstable and can convert to other phenotypes, especially Th1, both in vitro and in vivo. T(regs) are generated from naive precursors both in the thymus (natural, nT(regs)) and in the periphery (induced, iT(regs)). The highly suppressive function of T(regs) enables them to control many inflammatory diseases in animals and makes them particularly attractive candidates for immunotherapy in humans. The stability of the T(reg) phenotype is therefore of paramount importance in this context. Recent descriptions of T(reg) biology have suggested that components of pathogens or inflammatory mediators may subvert the suppressive function of T(regs) in order to allow propagation of adequate immune responses. Unexpectedly, however, a number of groups have now described conversion of T(regs) to the Th17 phenotype induced by appropriate inflammatory stimuli. These observations are particularly relevant in the context of cell therapy but may also explain some of the dysregulation seen in autoimmune diseases. In this paper, we review T(reg) to Th17 conversion and propose some potential mechanisms for this phenomenon.

143: PloS one, 2009, 4(11)
Tumor-Like Stem Cells Derived from Human Keloid Are Governed by the Inflammatory Niche Driven by IL-17/IL-6 Axis.

[Abstract]BACKGROUND: Alterations in the stem cell niche are likely to contribute to tumorigenesis; however, the concept of niche promoted benign tumor growth remains to be explored. Here we use keloid, an exuberant fibroproliferative dermal growth unique to human skin, as a model to characterize benign tumor-like stem cells and delineate the role of their "pathological" niche in the development of the benign tumor. METHODS AND FINDINGS: Subclonal assay, flow cytometric and multipotent differentiation analyses demonstrate that keloid contains a new population of stem cells, named keloid derived precursor cells (KPCs), which exhibit clonogenicity, self-renewal, distinct embryonic and mesenchymal stem cell surface markers, and multipotent differentiation. KPCs display elevated telomerase activity and an inherently upregulated proliferation capability as compared to their peripheral normal skin counterparts. A robust elevation of IL-6 and IL-17 expression in keloid is confirmed by cytokine array, western blot and ELISA analyses. The altered biological functions are tightly regulated by the inflammatory niche mediated by an autocrine/paracrine cytokine IL-17/IL-6 axis. Utilizing KPCs transplanted subcutaneously in immunocompromised mice we generate for the first time a human keloid-like tumor model that is driven by the in vivo inflammatory niche and allows testing of the anti-tumor therapeutic effect of antibodies targeting distinct niche components, specifically IL-6 and IL-17. CONCLUSIONS/SIGNIFICANCE: These findings support our hypothesis that the altered niche in keloids, predominantly inflammatory, contributes to the acquirement of a benign tumor-like stem cell phenotype of KPCs characterized by the uncontrolled self-renewal and increased proliferation, supporting the rationale for in vivo modification of the "pathological" stem cell niche as a novel therapy for keloid and other mesenchymal benign tumors.

144: Current medicinal chemistry, 2009 Nov 5, 4(11)
Gammadelta T Lymphocytes Producing Ifngamma and Il-17 In Response To Candida Albicans Or Mycobacterial Antigens: Possible Implications For Acute And Chronic Inflammation.

[Abstract]T lymphocytes bearing the gammadelta T cell receptor are known to play an important role in the first-line defense against viral, bacterial and fungal pathogens. Two main subsets of gammadelta T cells are known, showing distinct functional behaviour: Vdelta2 T lymphocytes, circulating in the peripheral blood, are involved in the response to mycobacterial infections and certain viruses, including coxsakie virus B3 and herpes simplex virus type 2. Vdelta1 T cells are resident in the mucosal-associated lymphoid tissue and are reported to participate in the immunity against Listeria monocytogenes and cytomegalovirus. Vdelta2 T lymphocytes recognize non-peptidic phosphorylated metabolites of isoprenoid biosynthesis, expressed by mycobacteria, while Vdelta1 T cells mainly interact with MHC-related antigens (MIC-A and MIC-B) and with receptors, called UL-16 binding proteins, for the UL-16 protein produced by cytomegalovirus-infected cells. Both Vdelta1 and Vdelta2 T cells can produce interferon-gamma in response to MIC-A(+) cells or non-peptide antigens, respectively. Moreover, production of TNF-alpha by human Vgamma9/Vdelta2 T cells has been demonstrated in response to bacterial products and non-peptidic molecules. Recently, it has been reported that gammadelta T lymphocytes can produce IL-17 during Escherichia coli or Mycobacterium tuberculosis infections in mice. This is of interest as IL-17 is emerging as a cytokine crucial in the control of intracellular pathogens and fungi. In this review, we will discuss the possible role of IL-17 producing gammadelta T cells in the regulation of acute and chronic inflammation, focusing on the different response of the two subsets to mycobacterial, viral or fungal antigens.

145: The Journal of allergy and clinical immunology, 2009 Nov, 124(5)
Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes.

[Abstract]BACKGROUND: TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear. OBJECTIVE: To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to compare genomic profiles of patients who responded or did not respond to treatment. METHODS: In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n = 15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time points during drug treatment (baseline and weeks 1, 2, 4, and 12) compared with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time. RESULTS: In responders, 4 clusters of downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels. CONCLUSION: Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the T(H)17 immune response.

146: Journal of immunology (Baltimore, Md. : 1950), 2009 Nov 4, 87(3)
Natural Occurring IL-17 Producing T Cells Regulate the Initial Phase of Neutrophil Mediated Airway Responses.

[Abstract]Effector Th17 cells are a major source of IL-17, a critical inflammatory cytokine in autoimmune diseases and in host defenses during bacterial infections. Recently, splenic lymphoid tissue inducer-like cells have been reported to be a source of T cell independent IL-17. In this study, we report that the immune system contains a unique set of natural occurring IL-17 producing cell, "natural" Th17 (nTh17), which are a memory-like T cell subset. The nTh17 cells can develop in the absence of the IL-6/STAT3 signaling axis required by inducible Th17 cells. The nTh17 cell population is distinct from conventional inducible Th17 cells, since nTh17 cells express substantial amounts of IL-17A (IL-17), but not IL-17F, under the control of the master regulator, RORgammat. The nTh17 cells simultaneously produce IFN-gamma. DO11.10 transgenic mice with a Rag(-/-) background (DO11.10 Rag(-/-)) lack nTh17 cells, and, following intranasal administration of OVA, IL-17-dependent neutrophil infiltration occurs in DO11.10 transgenic mice, but not in DO11.10 Rag(-/-) mice. The impaired neutrophil-dependent airway response is restored by adaptive transfer of nTh17 cells into DO11.10 Rag(-/-) mice. These results demonstrate that a novel T cell subset, nTh17, facilitates the early phase of Ag-induced airway responses and host defenses against pathogen invasion before the establishment of acquired immunity.

147: Rheumatology international, 2009 Nov 4, 87(3)
IL-23 and IL-17 in ankylosing spondylitis.

[Abstract]In the absence of IL-10, colonic inflammation ensues, which is characterized by high levels of IL-17. Here, we demonstrate a direct correlation between ICOS expression and IL-17 production in cIELs. IL-10(-/-) mice had increased numbers of cIELs and greater colon weight. Although the CD69 early activation antigen was expressed on cIELs from normal and IL-10(-/-) mice, ICOS was expressed only on cIELs from IL-10(-/-) mice. IL-17-producing cells in IL-10(-/-) mice consisted of CD4(+) and CD8(+) cIELs; however, CD4(+) cells were the predominant IL-17-producing cell population. Culture of cIELs from IL-10(-/-) mice with IL-23 resulted in an increase in ICOS and IL-17 expression, whereas IL-10 suppressed expression of ICOS and IL-17. This occurred in primary cultures and recall stimulation experiments. The ICOS ligand B7RP-1 was up-regulated on colonic epithelial cells and on a population of large granular leukocytes during inflammation. Culture of cIELs with B7RP-1(+) DCs enhanced IL-17A production from normal cIELs but failed to do so using cIELs from ICOS(-/-) mice. In vivo treatment of IL-10(-/-) mice with antibody to ICOS resulted in a significant reduction in colonic pathology. These findings implicate ICOS as an activational signal of Th17 cells during chronic intestinal inflammation, and they suggest that under some conditions, control of ICOS expression may help to suppress chronic intestinal inflammation.

148: Immunity, 2009 Oct 21, 114(17)
Interleukin-17 Is Required for T Helper 1 Cell Immunity and Host Resistance to the Intracellular Pathogen Francisella tularensis.

[Abstract]The importance of T helper type 1 (Th1) cell immunity in host resistance to the intracellular bacterium Francisella tularensis is well established. However, the relative roles of interleukin (IL)-12-Th1 and IL-23-Th17 cell responses in immunity to F. tularensis have not been studied. The IL-23-Th17 cell pathway is critical for protective immunity against extracellular bacterial infections. In contrast, the IL-23-Th17 cell pathway is dispensable for protection against intracellular pathogens such as Mycobacteria. Here we show that the IL-23-Th17 pathway regulates the IL-12-Th1 cell pathway and was required for protective immunity against F.tularensis live vaccine strain. We show that IL-17A, but not IL-17F or IL-22, induced IL-12 production in dendritic cells and mediated Th1 responses. Furthermore, we show that IL-17A also induced IL-12 and interferon-gamma production in macrophages and mediated bacterial killing. Together, these findings illustrate a biological function for IL-17A in regulating IL-12-Th1 cell immunity and host responses to an intracellular pathogen.

149: Rheumatology international, 2009 Oct 22,
The effects of adalimumab and methotrexate treatment on peripheral Th17 cells and IL-17/IL-6 secretion in rheumatoid arthritis patients.

[Abstract]Objective of the study is to assess the effects of adalimumab and MTX therapy on peripheral Th17 cells and IL-17/IL-6 secretion in RA patients. Twenty active RA patients were treated with oral MTX 15 mg per week (MTX group, n = 10), or hypodermal adalimumab 40 or 80 mg every other week (ADA group, n = 10). Peripheral blood samples were taken for laboratory evaluation at week 0 and week 12 of treatment, including flowcytometric detection of peripheral CD4(+) IL-17(+) cells, RT-PCR detection of mRNA expressions of IL-17, RORc and FoxP3, and ELISA determination of serum IL-17 and IL-6. Ten age and sex marched healthy volunteers were included as normal controls. Results showed that (1) DAS28 in both groups improved at week 12 compared to week 0 (3.9 +/- 1.3 vs. 6.4 +/- 1.4 and 3.2 +/- 0.9 vs. 5.2 +/- 0.9, respectively). (2) The percentage and MFI of peripheral CD4(+) IL-17(+) cells in RA patients were significantly higher comparing to normal controls (1.64 +/- 0.97% vs. 0.75 +/- 0.20%, p < 0.01; and 29.8 +/- 9.7 vs. 19.8 +/- 4.6, p < 0.05, respectively), and positively correlated with ESR and DAS28. Peripheral Th17 cells and serum IL-6 in RA patients decreased after treatment (from 1.60 +/- 0.78% to 1.28 +/- 0.41%, and from 17.15 +/- 14.53 pg/ml to 6.97 +/- 5.51 pg/ml, p < 0.05, respectively). Peripheral FoxP3 mRNA expression in active RA patients was significantly lower comparing to normal controls, and negatively correlated with ESR. Baseline Th17 percentage of RA patients negatively correlated with DAS28 improvement after treatment. In conclusion, adalimumab and MTX treatment down regulates peripheral Th17 cells and serum IL-6 level in RA patients. Baseline Th17 level negatively predicts the effect of adalimumb/MTX treatment.

150: Journal of immunology (Baltimore, Md. : 1950), 2009 Nov 1, 183(9)
Cyclooxygenase-1 orchestrates germinal center formation and antibody class-switch via regulation of IL-17.

[Abstract]The cyclooxygenase (COX) enzymes are known modulators of innate immune cell function; however, their contributions to adaptive immunity are relatively unknown. We investigated the roles of COX-1 and COX-2 in the humoral immune response to infection with the Lyme disease pathogen Borrelia burgdorferi. We report that in vitro, murine B cells constitutively expressed COX-1 and up-regulated expression of both COX-1 and COX-2 as well as their products PGE(2), PGF(2alpha), and thromboxane B(2) and their receptors following stimulation with B. burgdorferi or anti-CD40. In vitro inhibition of COX-1 and/or COX-2 in murine B cells resulted in decreased eicosanoid production and altered Ab production. Importantly, infection of mice lacking COX-1, but not COX-2, activity resulted in a defect in Ig class-switching and a lack of Borrelia-specific IgG production. This defect correlated with decreased germinal center formation and IL-6 and IL-17 production, and it could be partially recovered by restoration of IL-6, but fully recovered by IL-17. Furthermore, sera from COX-1 inhibitor-treated mice were dramatically less effective in killing B. burgdorferi, but borreliacidal activity was restored in COX-1 inhibitor-treated mice administered IL-17. We conclude that IL-17 plays a role in Ab production and Ig class-switching in response to infection and that COX-1 is a critical, previously unrecognized regulator of this response.

151: Hepatology (Baltimore, Md.), 2009 Sep 9, 183(9)
Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B.

[Abstract]Interleukin-17 (IL-17)-producing CD4(+) T cells (Th17)-mediated immune response has been demonstrated to play a critical role in inflammation-associated disease; however, its role in chronic hepatitis B virus (HBV) infection remains unknown. Here we characterized peripheral and intrahepatic Th17 cells and analyzed their association with liver injury in a cohort of HBV-infected patients including 66 with chronic hepatitis B (CHB), 23 with HBV-associated acute-on-chronic liver failure (ACLF), and 30 healthy subjects as controls. The frequency of circulating Th17 cells increased with disease progression from CHB (mean, 4.34%) to ACLF (mean, 5.62%) patients versus healthy controls (mean, 2.42%). Th17 cells were also found to be largely accumulated in the livers of CHB patients. The increases in circulating and intrahepatic Th17 cells positively correlated with plasma viral load, serum alanine aminotransferase levels, and histological activity index. In vitro, IL-17 can promote the activation of myeloid dendritic cells and monocytes and enhance the capacity to produce proinflammatory cytokines IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and IL-23 in both CHB patients and healthy subjects. In addition, the concentration of serum Th17-associated cytokines was also increased in CHB and ACLF patients. Conclusion: Th17 cells are highly enriched in both peripheral blood and liver of CHB patients, and exhibit a potential to exacerbate liver damage during chronic HBV infection. (HEPATOLOGY 2009.).

152: Nature immunology, 2009 Oct 18, 183(9)
Structural basis of receptor sharing by interleukin 17 cytokines.

[Abstract]Interleukin 17 (IL-17)-producing helper T cells (T(H)-17 cells), together with their effector cytokines, including members of the IL-17 family, are emerging as key mediators of chronic inflammatory and autoimmune disorders. Here we present the crystal structure of a complex of IL-17 receptor A (IL-17RA) bound to IL-17F in a 1:2 stoichiometry. The mechanism of complex formation was unique for cytokines and involved the engagement of IL-17 by two fibronectin-type domains of IL-17RA in a groove between the IL-17 homodimer interface. Binding of the first receptor to the IL-17 cytokines modulated the affinity and specificity of the second receptor-binding event, thereby promoting heterodimeric versus homodimeric complex formation. IL-17RA used a common recognition strategy to bind to several members of the IL-17 family, which allows it to potentially act as a shared receptor in multiple different signaling complexes.

153: Science signaling, 2009, 2(92)
Act1, a U-box E3 ubiquitin ligase for IL-17 signaling.

[Abstract]Interleukin-17 (IL-17), a proinflammatory cytokine mainly produced by cells of the T helper 17 (T(H)17) lineage, is required for host defense against bacterial and fungal infections and plays a critical role in the pathogenesis of inflammatory and autoimmune diseases. Act1 is an essential adaptor molecule in IL-17-mediated signaling and is recruited to the IL-17 receptor (IL-17R) upon IL-17 stimulation through an interaction between its SEFIR domain and that of the IL-17R. Here, we report that Act1 is a U-box E3 ubiquitin ligase and that its activity is essential for IL-17-mediated signaling pathways. Through the use of the Ubc13-Uev1A E2 complex, Act1 mediated the lysine-63-linked ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6), a component of IL-17-mediated signaling. Deletion and point mutations of the Act1 U-box abolished Act1-mediated ubiquitination of TRAF6 and impaired the ability of Act1 to restore IL-17-dependent signaling and expression of target genes in Act1(-/-) mouse embryonic fibroblasts. We also showed that the lysine-124 residue of TRAF6 was critical for efficient Act1-mediated ubiquitination of TRAF6 and for the ability of TRAF6 to mediate IL-17-induced activation of nuclear factor kappaB. Thus, we propose that Act1 mediates IL-17-induced signaling pathways through its E3 ubiquitin ligase activity and that TRAF6 is a critical substrate of Act1, which indicates the importance of protein ubiquitination in the IL-17-dependent inflammatory response.

154: Science signaling, 2009, 2(92)
IL-17 receptor signaling: ubiquitin gets in on the act.

[Abstract]Engagement of the interleukin-17 (IL-17) receptor complex triggers activation of the transcription factor nuclear factor kappaB (NF-kappaB). A wide array of signaling molecules can contribute to the activation of NF-kappaB, but a number of common themes link the receptors engaged to activate it with the translocation of the active complex to the nucleus; among these is a clear role for ubiquitination. Ubiquitination is essential to the degradation of the inhibitor of NF-kappaB (IkappaB) subunits, which otherwise retain the inactive NF-kappaB complex in the cytosol. However, additional roles for ubiquitination in the assembly of signaling complexes and in enzyme activation are underappreciated aspects of NF-kappaB induction pathways. These roles require a form of ubiquitination biochemically distinct from that which targets proteins for degradation. The identification of Act1, an adaptor protein of the IL-17 receptor, as an E3 ubiquitin ligase capable of initiating this modification provides an impressive connection between the IL-17 receptor complex and pathways that activate NF-kappaB.

155: Immunology, 2009 Aug 4, 2(92)
Interleukin-17-producing gammadelta(+) T cells protect NOD mice from type 1 diabetes through a mechanism involving transforming growth factor-beta.

[Abstract]Summary Whether interleukin (IL)-17 promotes a diabetogenic response remains unclear. Here we examined the effects of neutralization of IL-17 on the progress of adoptively transferred diabetes. IL-17-producing cells in non-obese diabetic (NOD) mice were identified and their role in the pathogenesis of diabetes examined using transfer and co-transfer assays. Unexpectedly, we found that in vivo neutralization of IL-17 did not protect NOD-severe combined immunodeficiency (SCID) mice against diabetes transferred by diabetic splenocytes. In NOD mice, gammadelta(+) T cells were dominated by IL-17-producing cells and were found to be the major source of IL-17. Interestingly, these IL-17-producing gammadelta T cells did not exacerbate diabetes in an adoptive transfer model, but had a regulatory effect, protecting NOD mice from diabetes by up-regulating transforming growth factor (TGF)-beta production. Our data suggest that the presence of IL-17 did not increase the chance of the development of diabetes; gammadelta T cells protected NOD mice from diabetes in a TGF-beta-dependent manner, irrespective of their role as major IL-17 producers.

156: Infection and immunity, 2009 Oct 12, 2(92)
Superantigenic Staphylococcus aureus stimulate production of IL-17 from memory but not naive T cells.

[Abstract]T helper 17 (Th17) cells are characterized by their production of IL-17 and have a role in the protection against infections and in certain inflammatory diseases. Humans who lack Th17 cells are more susceptible to Staphylococcus aureus infections compared to individuals having Th17 cells. S. aureus is part of the commensal skin microflora and also colonize the infant gut. To investigate if UV-killed S. aureus would be more capable of inducing IL-17 than other commensal bacteria, we stimulated mononuclear cells from adults, infants and newborns with various Gram-positive and Gram-negative commensal bacteria. IL-17 was produced from adult memory Th17 cells after stimulation with superantigen-producing S. aureus, but not non-superantigenic S. aureus or other common commensal gut bacteria. Cells from newborns were poor IL-17 producers after stimulation with S. aureus, while in some cases IL-17 was secreted from cells isolated from infants at the age of 4 and 18 months. These results suggest that superantigenic S. aureus are particularly efficient in stimulating IL-17 production, and that the cytokine is produced from memory T cells.

157: The Journal of allergy and clinical immunology, 2009 Oct, 124(4)
Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13.

[Abstract]BACKGROUND: Atopic dermatitis (AD) is characterized by local and systemic T(H)2 responses to cutaneously introduced allergens and is a risk factor for asthma. Blockade of T(H)2 cytokines has been suggested as therapy for AD. OBJECTIVES: We sought to examine the effect of the absence of IL-4 and IL-13 on the T(H)17 response to epicutaneous sensitization in a murine model of allergic skin inflammation with features of AD. METHODS: Wild-type, IL4 knockout (KO), IL13 KO and IL4/13 double KO (DKO) mice were subjected to epicutaneous sensitization with ovalbumin (OVA) or saline and airway challenged with OVA. Systemic immune responses to OVA, skin and airway inflammation, and airway hyperresponsiveness were examined. RESULTS: OVA-sensitized DKO mice exhibited impaired T(H)2-driven responses with undetectable OVA-specific IgE levels and severely diminished eosinophil infiltration at sensitized skin sites but intact dermal infiltration with CD4(+) cells. DKO mice mounted exaggerated IL-17A but normal IFN-gamma and IL-5 systemic responses. Airway challenge of these mice with OVA caused marked upregulation of IL-17 mRNA expression in the lungs, increased neutrophilia in bronchoalveolar lavage fluid, airway inflammation characterized by mononuclear cell infiltration with no detectable eosinophils, and bronchial hyperresponsiveness to methacholine that were reversed by IL-17 blockade. IL-4, but not IL-13, was identified as the major T(H)2 cytokine that downregulates the IL-17 response in epicutaneously sensitized mice. CONCLUSION: Epicutaneous sensitization in the absence of IL-4/IL-13 induces an exaggerated T(H)17 response systemically and in lungs after antigen challenge that results in airway inflammation and airway hyperresponsiveness.

158: Journal of immunology (Baltimore, Md. : 1950), 2009 Nov 1, 183(9)
IL-17/Th17 promotes type 1 T cell immunity against pulmonary intracellular bacterial infection through modulating dendritic cell function.

[Abstract]Although their contribution to host defense against extracellular infections has been well defined, IL-17 and Th17 are generally thought to have limited impact on intracellular infections. In this study, we investigated the role and mechanisms of IL-17/Th17 in host defense against Chlamydia muridarum, an obligate intracellular bacterium, lung infection. Our data showed rapid increase in IL-17 production and expansion of Th17 cells following C. muridarum infection and significant detrimental impact of in vivo IL-17 neutralization by anti-IL-17 mAb on disease course, immune response, and dendritic cell (DC) function. Specifically, IL-17-neutralized mice exhibited significantly greater body weight loss, higher organism growth, and much more severe pathological changes in the lung compared with sham-treated control mice. Immunological analysis showed that IL-17 neutralization significantly reduced Chlamydia-specific Th1 responses, but increased Th2 responses. Interestingly, the DC isolated from IL-17-neutralized mice showed lower CD40 and MHC II expression and IL-12 production, but higher IL-10 production compared with those from sham-treated mice. In two DC-T cell coculture systems, DC isolated from IL-17-neutralized mice induced higher IL-4, but lower IFN-gamma production by Ag-specific T cells than those from sham-treated mice in cell priming and reaction settings. Adoptive transfer of DC isolated from IL-17-neutralized mice, unlike those from sham-treated mice, failed to protect the recipients against challenge infection. These findings provide in vivo evidence that IL-17/Th17 plays an important role in host defense against intracellular bacterial infection, and suggest that IL-17/Th17 can promote type 1 T cell immunity through modulating DC function.

159: Journal of immunology (Baltimore, Md. : 1950), 2009 Nov 1, 183(9)
Regulation of gastric B cell recruitment is dependent on IL-17 receptor a signaling in a model of chronic bacterial infection.

[Abstract]Th17-driven immune responses contribute to the pathogenesis of many chronic inflammatory diseases. In this study, we investigated the role of IL-17 signaling in chronic gastric inflammation induced by Helicobacter pylori, a Gram-negative bacterium that persistently colonizes the human stomach. Wild-type C57BL/6 mice and mice lacking IL-17RA (IL-17RA(-/-)) were orogastrically infected with H. pylori. Differences in bacterial colonization density and gastric inflammation were not apparent at 1 mo postinfection, but by 3 mo postinfection, H. pylori colonization density was higher and mononuclear gastric inflammation more severe in infected IL-17RA(-/-) mice than in infected wild-type mice. A striking feature was a marked increase in gastric B cells, plasma cells, and lymphoid follicles, along with enhanced H. pylori-specific serum Ab responses, in infected IL-17RA(-/-) mice. Fewer gastric neutrophils and lower levels of neutrophil-recruiting chemokines were detected in infected IL-17RA(-/-) mice than in infected wild-type mice. Gastric IL-17a and IL-21 transcript levels were significantly higher in infected IL-17RA(-/-) mice than in infected wild-type mice or uninfected mice, which suggested that a negative feedback loop was impaired in the IL-17RA(-/-) mice. These results underscore an important role of IL-17RA signaling in regulating B cell recruitment. In contrast to many chronic inflammatory diseases in which IL-17RA signaling promotes an inflammatory response, IL-17RA signaling down-regulates the chronic mononuclear inflammation elicited by H. pylori infection.

160: Journal of neuroimmunology, 2009 Oct 1, 183(9)
Decreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders.

[Abstract]A potential role for T(H)17 cells has been suggested in a number of conditions including neurodevelopmental disorders such as autism spectrum disorders (ASD). In the current study, we investigated cellular release of IL-17 and IL-23 following an in-vitro immunological challenge of peripheral blood mononuclear cells (PBMC) from children with ASD compared to age-matched typically developing controls. Following stimulation, the concentration of IL-23, but not IL-17, was significantly reduced (p=0.021) in ASD compared to controls. Decreased cellular IL-23 production in ASD warrants further research to determine its role on the generation and survival of T(H)17 cells, a cell subset important in neuroinflammatory conditions that may include ASD.

161: Nature reviews. Rheumatology, 2009 Oct, 5(10)
IL-17 as a future therapeutic target for rheumatoid arthritis.

[Abstract]The discovery of interleukin (IL)-17 and its major cell source, the type 17 T-helper (TH17) lymphocyte, has been a major step in the understanding of erosive arthritis. This Review summarizes current knowledge of the role of IL-17 in this context derived from both animal models and studies in patients with rheumatoid arthritis. Evidence shows that IL-17 is present at sites of inflammatory arthritis and that, in synergistic interactions, it amplifies the inflammation induced by other cytokines, primarily tumor necrosis factor. In several animal models of arthritis, inhibition of IL-17 limits inflammation and joint erosion. Initial observations from phase I trials show that signs and symptoms of RA are significantly suppressed following treatment with anti-IL-17 antibodies, without notable adverse effects. The emergence of IL-17 blockade as a future therapy in rheumatoid arthritis is highlighted, along with the potential goals and limitations of this therapeutic approach.

162: Journal of immunology (Baltimore, Md. : 1950), 2009 Oct 15, 183(8)
Development of allergen-induced airway inflammation in the absence of T-bet regulation is dependent on IL-17.

[Abstract]Dysfunctional expression of T-bet, a transcription factor that is critical for IFN-gamma production, has been implicated in the development of asthma. To investigate in detail the mechanisms responsible for exacerbated disease in the absence of T-bet expression, BALB/c wild-type (WT) and T-bet(-/-) mice were used in a murine model of OVA-induced allergic lung inflammation. Following OVA challenge, T-bet(-/-) mice displayed increased histological inflammation in the lungs as well as greater thickening of the bronchiole linings, increased numbers of eosinophils and neutrophils in the lung, and enhanced airway hyperresponsiveness, compared with WT mice. However, the production of Th2 cytokines in T-bet(-/-) mice did not appear to be significantly greater than in WT mice. Interestingly, a marked increase in the levels of the proinflammatory cytokine IL-17 was observed in T-bet(-/-) mice. Neutralization of pulmonary IL-17 in T-bet(-/-) mice by anti-IL-17 mAb treatment during OVA challenge resulted in decreased levels of neutrophilic infiltration into the airways and decreased airway inflammation, essentially reversing the development of allergic asthma development. These findings indicate that IL-17 is a key mediator of airway inflammation in the absence of T-bet. The results of this study suggest a possible target for therapeutic intervention of human asthma.

163: Veterinary immunology and immunopathology, 2009 Aug 19, 183(8)
Expressed gene sequences of the equine cytokines interleukin-17 and interleukin-23.

[Abstract]This report describes the initial cloning and characterization of the equine interleukin-17 (IL-17) expressed gene sequence from mRNA obtained from equine intestinal tissue and interleukin-23 (IL-23) expressed gene sequence from mRNA obtained from equine peripheral blood mononuclear cells. Equine IL-17 has 462 nucleotides in the translated region, determined by homology with known human and mouse sequences, and shares 84% and 75% identity, respectively. For the deduced amino acid sequences, the identity with human and mouse is 76% and 70%. Equine IL-23 has 579 nucleotides in the translated region. Homology with known human and mouse sequences was determined to be 89% and 77%. Deduced amino acid identities are 89% with the human sequence and 70% with the mouse sequence. The gene sequences were identified as part of the U.S. Veterinary Immune Reagent Network with a goal of developing reagents in order to aid veterinary researchers in the investigation of diseases in livestock species.

164: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2009 Sep 16, 183(8)
Interleukin 17 is not required for autoimmune-mediated pathological damage during chronic graft versus host disease.

[Abstract]The transition from acute to chronic graft versus host disease (GVHD) is characterized by the progressive loss of self tolerance and the development of autoimmune manifestations. Interleukin 17 (IL-17) is a proinflammatory cytokine that has been shown to play a prominent role in autoimmune disorders in the nontransplant setting, but the extent to which IL-17 is necessary for the autoimmunity that occurs as a consequence of GVHD is not known. In this study, we demonstrate using a combination of antibody-based and genetic approaches that IL-17 is not required for the loss of self tolerance and resulting CD4(+)T cell-dependent pathological damage which occurs during the evolution from acute to chronic GVHD. Rather, T(H)1 cells and other proinflammatory cytokines are fully competent to promote autoimmune-mediated tissue damage. Thus, the selective targeting of IL-17 may not be a viable clinical strategy for preventing the autoimmune manifestations that develop during chronic GVHD.

165: Current rheumatology reports, 2009 Oct, 11(5)
The role of interleukin-17 in the pathogenesis of rheumatoid arthritis.

[Abstract]Interleukin (IL)-17 (also known as IL-17A), the signature cytokine of the newly described T helper 17 (Th17) cell population, has been implicated in the pathogenesis of numerous autoimmune diseases including rheumatoid arthritis. IL-17 is the founding member of a new subclass of cytokines that have highly proinflammatory properties. Studies in rodents and mammalian cell culture systems, as well as clinical settings, support a role for IL-17 in promoting rheumatoid arthritis. This article discusses the history of the discovery of Th17 cells, the potential mechanisms of action of IL-17 in autoimmunity, and perspectives for IL-17-targeted cytokine therapy.

166: Journal of immunology (Baltimore, Md. : 1950), 2009 Oct 1, 183(7)
Protumor vs antitumor functions of IL-17.

[Abstract]Inflammation appears to be a necessity for both metastasis and elimination of tumor cells. IL-17, a proinflammatory cytokine produced by Th17 cells, contributes to both the processes by playing a dual role in the antitumor immunity. On one hand, IL-17 promotes an antitumor cytotoxic T cell response leading to tumor regression. On the other hand, by facilitating angiogenesis and egress of tumor cells from the primary focus, IL-17 promotes tumor growth. Thus, the therapeutic application that uses IL-17 needs to be refined by minimizing its protumor functions.

167: PloS one, 2009, 4(9)
Pertussis toxin stimulates IL-17 production in response to Bordetella pertussis infection in mice.

[Abstract]In a mouse model of respiratory tract infection by Bordetella pertussis, bacteria multiply in the airways over the first week and are then cleared over the next 3-4 weeks by the host immune response. Pertussis toxin (PT), a virulence factor secreted exclusively by B. pertussis, promotes bacterial growth in the airways by suppression and modulation of host immune responses. By comparison of wild type and PT-deficient strains, we examined the role of PT in modulating airway cytokine and chemokine responses affecting neutrophil recruitment during B. pertussis infection in mice. We found that, despite early inhibition of neutrophil recruitment by PT, high numbers of neutrophils were recruited to the airways by 4 days post-infection with the wild type strain, but not with the PT-deficient strain, and that this correlated with upregulation of neutrophil-attracting chemokine gene expression. In addition, there was similar upregulation of genes expressing the cytokines IL-17A (IL-17), TNF-alpha and IFN-gamma, indicating a mixed Th1/Th17 response. Expression of IL-6, a cytokine involved in Th17 induction, was upregulated earlier than the IL-17 response. We showed that PT, rather than bacterial numbers, was important for induction of these responses. Flow cytometric analysis revealed that the IL-17-producing cells were macrophages and neutrophils as well as T cells, and were present predominantly in the airways rather than the lung tissue. Antibody neutralization of IL-17 significantly reduced chemokine gene expression and neutrophil recruitment to the airways, but only modestly increased peak bacterial loads. These data indicate that PT stimulates inflammatory responses by induction of Th1- and Th17-associated cytokines, including IL-17, during B. pertussis infection in mice, but a role for IL-17 in protection against the infection remains to be established.

168: The Journal of infectious diseases, 2009 Oct 15, 200(8)
Impaired interferon-gamma responses, increased interleukin-17 expression, and a tumor necrosis factor-alpha transcriptional program in invasive aspergillosis.

[Abstract]BACKGROUND: Invasive aspergillosis (IA) is the most common cause of death associated with fungal infection in the developed world. Historically, susceptibility to IA has been associated with prolonged neutropenia; however, IA has now become a major problem in patients on calcineurin inhibitors and allogenic hematopoietic stem cell transplant patients following engraftment. These observations suggest complex cellular mechanisms govern immunity to IA. METHODS: To characterize the key early events that govern outcome from infection with Aspergillus fumigatus, we performed a comparative immunochip microarray analysis of the pulmonary transcriptional response to IA between cyclophosphamide-treated mice and immunocompetent mice at 24 h after infection. RESULTS: We demonstrate that death due to infection is associated with a failure to generate an incremental interferon-gamma response, increased levels of interleukin-5 and interleukin-17a transcript, coordinated expression of a network of tumor necrosis factor-alpha-related genes, and increased levels of tumor necrosis factor-alpha. In contrast, clearance of infection is associated with increased expression of a number genes encoding proteins involved in innate pathogen clearance, as well as apoptosis and control of inflammation. CONCLUSION: This first organ-level immune response transcriptional analysis for IA has enabled us to gain new insights into the mechanisms that govern fungal immunity in the lung.

169: Journal of cellular biochemistry, 2009 Nov 1, 108(4)
IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: A novel mechanism of osteoclastogenesis by IL-17.

[Abstract]IL-17 is a proinflammatory cytokine crucial for osteoclastic bone resorption in the presence of osteoblasts or synoviocytes in rheumatoid arthritis. However, the role of IL-17 in osteoclastogenesis from human monocytes alone remains unclear. Here, we investigated the role of IL-17 in osteoclastogenesis from human monocytes alone and the direct effect of infliximab on the osteoclastogenesis induced by IL-17. Human peripheral blood mononuclear cells (PBMC) were cultured for 3 days with M-CSF. After non-adherent cells were removed, IL-17 was added with either infliximab or osteoprotegerin (OPG). Seven days later, adherent cells were stained for vitronectin receptor. On the other hand, CD11b-positive monocytes purified from PBMC were also cultured and stained as described above. CD11b-positive cells were cultured with TNF-alpha and receptor activator of NF-kappaB ligand (RANKL). In the cultures of both adherent cells and CD11b-positive cells, IL-17 dose-dependently induced osteoclastogenesis in the absence of soluble-RANKL. OPG or infliximab inhibited IL-17-induced osteoclastogenesis. Interestingly, in the culture of CD11b-positive cells, the osteoclastogenesis was more potently inhibited by infliximab than by OPG. TNF-alpha and RANKL synergistically induced osteoclastogenesis. The present study clearly demonstrated the novel mechanism by which IL-17 directly induces osteoclastogenesis from human monocytes alone. In addition, infliximab potently inhibits the osteoclastogenesis directly induced by IL-17. J. Cell. Biochem. 108: 947-955, 2009. (c) 2009 Wiley-Liss, Inc.

170: Cytokine, 2009 Dec, 48(3)
IL-17 inhibits human Th1 differentiation through IL-12Rbeta2 downregulation.

[Abstract]Th17 cells are critical in adaptive immunity and autoimmune disease. The polarized development of Th17, Th1 and Th2 cells is dependent on counterregulatory effects on each other. Whereas IFN-gamma inhibits Th17 development, the effect of IL-17 in human Th1 development is not known. We report a novel negative regulatory role of IL-17 on IL-12Rbeta2 expression associated with reduced IL-12 responsiveness. IL-17 decreased IL-12-induced IFN-gamma expression in PBMC and developing Th1 cells, associated with a selective reduction in IL-12Rbeta2, and not IL-23R, IL-12Rbeta1 or T-bet. Counterregulatory effects of human Th17 on Th1 lineage cytokines may contribute to lineage divergence. In autoimmune disease, IL-17 may reinforce its own developmental programme by reducing IL-12 responsiveness, thus limiting inhibitory effects of IFN-gamma on Th17 development.

171: Journal of neuroimmunology, 2009 Oct 30, 215(1-2)
Encephalitogenic T cells that stably express both T-bet and RORgammat consistently produce IFNgamma but have a spectrum of IL-17 profiles.

[Abstract]Th1/Th17 cells, secreting both IFNgamma and IL-17, are often associated with inflammatory pathology. We cloned and studied the cytokine phenotypes of MBP-specific, TCR-identical encephalitogenic CD4+ cells in relationship to Th1- and Th17-associated transcription factors T-bet and RORgammat. IFNgamma-producing cells could be sub-divided into those that are T-bet(+)/RORgammat(-) and those that are T-bet(+)/RORgammat(+). The latter comprises a spectrum of phenotypes, as defined by IL-17 production, and can be induced to up-regulate IL-23R with IL-12 or IL-23. The former, bona fide Th1 cells, lack IL-23R expression under all conditions. In vivo, T-bet(+)/RORgammat(-) and T-bet(+)/RORgammat(+) clones induce EAE equally well.

172: Journal of leukocyte biology, 2009 Dec, 86(6)
Retinal Astrocytes respond to IL-17 differently than Retinal Pigment Epithelial cells.

[Abstract]IL-17+ T cells make up the majority of the infiltrating cells in the inflamed eye during the development of EAU. However, the role of IL-17 in ocular inflammation is poorly defined. Given that the primary target cells for IL-17 are parenchymal cells of the tissue, we investigated the in vitro effect of IL-17 on mouse RACs and RPE cells. Our results showed that although RACs and RPE cells expressed the IL-17R, RACs responded to IL-17 by producing increased amounts of proinflammatory cytokines and chemokines, leading to increased migration of granulocytes, whereas RPE cells responded to the same concentration of IL-17 by expressing increased levels of SOCS proteins, resulting in only limited production of proinflammatory cytokines and chemokines and an increased amount of suppressive cytokines, such as LIF. The combination of IL-17 and IFN-gamma had a synergistic effect on cell migration with RACs but an antagonistic effect with RPE. In addition, specific inhibitors of the PI3K/Akt signaling pathway completely blocked inflammatory cell migration induced by chemokines released by IL-17-stimulated RACs. Our results demonstrate that IL-17 can induce a pro- or anti-inflammatory effect in the eye, depending on the parenchymal cells stimulated.

173: Immunology letters, 2009 Dec 2, 127(1)
Modulation of inflammation through IL-17 production by gammadelta T cells: mandatory in the mouse, dispensable in humans?

[Abstract]Recent studies suggest that gammadelta T cells are innate IL-17 producers owing to unique features of their developmental program. A key contribution of this subset to T helper 17 responses has been also suggested by numerous physiopathological studies mainly performed in mouse models. In the present review, we will summarize the main features of IL-17-producing gammadelta T cells and highlight the similarities and differences between murine gammadelta T cells and their human counterparts.

174: Veterinary immunology and immunopathology, 2009 Dec 15, 132(2-4)
Molecular characterization of duck interleukin-17.

[Abstract]Interleukin-17 (IL17), belonging to the Th17 family, is a proinflammatory cytokine produced by activated T cells. A 1034bp cDNA encoding duck IL17 (duIL17) was cloned from Con A-activated splenic lymphocytes of ducks. The encoded protein, which is predicted to consist of 169 amino acids, has a molecular weight of 18.8kDa and includes a 29 residue NH(2)-terminal signal peptide, a single potential N-linked glycosylation site, and six cysteine residues that are conserved in mammalian IL17. The duIL17 shared 84% amino acid sequence identity with the previously described chicken IL17 (chIL17), 36-47% to mammalian homologues, and open reading frame 13 of Herpesvirus saimiri (HVS13). The genomic structure of duIL17 was quite similar to its chicken and mammalian counterparts. The duIL17 mRNA expression was detected only in Con A-activated splenic lymphocytes by RT-PCR, although its expression was undetectable in a variety of normal tissues. Two mAbs against chIL17 showed cross-reactivity with duIL17 as detected by indirect ELISA and Western blot analysis. These findings indicate that the structure of IL17 is highly conserved among poultry, and two mAbs detecting common epitopes of IL17 are available for molecular and immunological studies of IL17 in birds.

175: Experimental & molecular medicine, 2009 Oct 31, 41(10)
Sequential evolution of IL-17 responses in the early period of allograft rejection.

[Abstract]In addition to CD4+CD25+Foxp3+ regulatory T (T(reg)) cells which protect against autoimmune tissue injury, IL-17-producing CD4+ T (T(h)17) cells have been recently described and shown to play a crucial role in autoimmune injury. It appears that there is a reciprocal developmental pathway between T(h)17 and T(reg) cells. Although IL-17 is known to be associated with allograft rejection, the cellular source of IL-17 and the nature of T(h)17 in the context of allograft rejection remain unknown. In the current study, the dynamics of T(reg) and IL-17-producing cells after syngeneic and allogeneic transplantation were examined using a wild-type murine cardiac transplantation model. Ly6G+ cells were found to produce IL-17 during the early postoperative period and CD8+ as well as CD4+ T cells were also found to produce IL-17 during alloimmune response. Graft-infiltrating Ly6G+, CD4+, and even CD8+ cells were found to express IL-17 highly compared to those in spleen. Although the frequencies of T(h)17 and T(reg) were found to gradually increase in both syngeneic and allogeneic recipients, T(h)17/T(reg) ratios were significantly higher in recipients with allograft rejection than in syngeneic recipients. In conclusion, IL-17 is produced by neutrophils during the early postoperative period and subsequently by T(h)17 and CD8+ T cells during allograft rejection. T(h)17/T(reg) imbalance is associated with the development of allograft rejection. This study would provide basic information on T(h)17 biology for future investigation in the field of transplantation.

176: Cell death and differentiation, 2009 Oct, 16(10)
IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling.

[Abstract]Interleukin-17 (IL-17) is a cytokine secreted primarily by T(H)-17 cells. Although IL-17 is primarily associated with the induction of tissue inflammation, the other biological roles of IL-17, including non-immune functions, have yet to be thoroughly explored. Here, we report that T-cell-produced IL-17 can induce proliferation of human bone marrow-derived mesenchymal stem cells (hMSCs) in a manner dependent on the generation of reactive oxygen species (ROS). Rac1 GTPase and NADPH oxidase 1 (Nox1) are activated by IL-17 to produce ROS, which in turn stimulates hMSC proliferation. The activation of the MEK-ERK pathway is also crucial for IL-17-dependent hMSC proliferation. TRAF6 and Act1 are required to activate Nox 1 and to phosphorylate MEK on IL-17 stimulation. Interestingly, IL-17 not only accelerates the proliferation of hMSCs, but also induces their migration, motility, and osteoblastic differentiation. Furthermore, IL-17 induces the expression of M-CSF and receptor activator of NF-kappaB ligand (RANKL) on hMSCs, thereby supporting osteoclastogenesis both in vivo and in vitro. On the basis of these results, we suggest that IL-17 can function as a signal to induce extensive bone turnover by regulating hMSC recruitment, proliferation, motility, and differentiation.

177: Experimental and molecular pathology, 2009 Dec, 87(3)
IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure.

[Abstract]OBJECTIVE: This study was designed to investigate whether IL-17 can regulate the expression of the MMP/TIMP system, the OPG/RANK/RANKL system, or type-I and type-III collagen fibers in a rat model of isoproterenol-induced heart failure (HF). We also investigated the effect of IL-17 on myocardial fibrosis in this model. METHODS: HF was induced in Wistar-Kyoto rats by hypodermic injection of isoproterenol (ISO) twice every 24 h. After 2 months, the surviving rats were divided into three groups: monoclonal Anti-IL-17 Ab (100 microg/day), IgG (100 microg/day) or PBS were injected five times every 48 h (i.p.). One day after the last injection, all of the rats were sacrificed. H&E and Masson staining were used to evaluate myocardial fibrosis, and immunohistochemistry was used to measure the levels of MMP-1, TIMP-1, TIMP-4, OPG, RANKL, type-I and type-III collagen fibers. We also treated adult rat cardiac fibroblasts with IL-17 (10 ng/ml), IL-17 (10 ng/ml)+OPG (10 ng/ml), IL-17 (10 ng/ml)+anti-RANKL Ab (100 ng/ml), or PBS for 24 h, realtime RT-PCR was used to measure the expressions of MMP-1. RESULTS: The expressions of MMP-1, RANKL, and type-I and -III collagen fibers decreased, and the expressions of TIMP-1, TIMP-4, and OPG increased in the Anti-IL-17 group compared to controls. H&E and Masson staining revealed that blockade of IL-17 can improve myocardial fibrosis in HF. IL-17 increased the expression of MMP-1 in cardiac fibroblasts, and OPG and anti-IL-17 Ab could inhibit this function partly. Thus, IL-17 was dependent on the RANKL/OPG system to induce MMP-1 partly. CONCLUSION: Our study demonstrates the contribution of IL-17 to myocardial fibrosis in isoproterenol-induced HF. IL-17 can regulate the RANKL/OPG and MMP/TIMP systems in this model. The RANKL/OPG system is one of intermediaries between IL-17 and MMP-1 in cardiac fibroblasts. As a harmful cytokine, anti-IL-17 treatment is a potential therapeutic strategy in HF.

178: Cellular and molecular neurobiology, 2009 Dec, 29(8)
IL-17 stimulates migration of carotid artery vascular smooth muscle cells in an MMP-9 dependent manner via p38 MAPK and ERK1/2-dependent NF-kappaB and AP-1 activation.

[Abstract]Inappropriate vascular remodeling is thought to be the main cause of restenosis following angioplasty. Migration of vascular smooth muscle cells (VSMC) into lumina, which is promoted by degradation of the extracellular matrix by matrix metalloproteinases (MMPs) plays a causal role in pathological vascular remodeling. The aim of the present research is to explore the effects of a novel cytokine, IL-17, on migration of VSMC and MMP-9 secretion. Carotid artery VSMC was isolated from Sprague-Dawley rats. Expression of MMP-9 and cell migration induced by IL-17 and its related signal pathway were detected. The results showed that IL-17-induced migration of VSMC in an MMP-9-dependent manner. IL-17-induced MMP-9 expression was via p38 MAPK and ERK1/2 dependent NF-kappaB and AP-1 activation. The present results demonstrated that IL-17 may play a role in vascular remodeling and targeting IL-17 or its specific downstream mediators is a potentially novel therapeutic pathway for attenuating the post-angioplastic restenosis.

179: Cytokine, 2009 Feb 28,
Interleukin-17 causes neutrophil mediated inflammation in ovalbumin-induced uveitis in DO11.10 mice.

[Abstract]T cell-mediated uveitis is strongly associated with many systemic inflammatory disorders. Th17 cells are a novel T cell subset characterized by production of interleukin (IL)-17. In this study, we used DO11.10 mice to investigate the role of IL-17 in the pathogenesis of uveitis. CD4(+) T cells in DO11.10 mice are genetically engineered to react with ovalbumin (OVA). IL-17 expression was determined by real-time PCR and ELISPOT. Uveitis was induced by intravitreal injection of OVA, and ocular inflammation was evaluated by intravital microscopy. OVA challenge significantly induced IL-17 production by DO11.10 splenocytes in vitro. Next, we examined whether OVA challenge could elicit local inflammation and induce IL-17 in vivo. OVA elicited marked neutrophil-predominant inflammatory cell infiltration in the eyes. This leukocyte influx was mediated by CD4(+) lymphocytes as evidenced by significant inhibition of the ocular inflammation by CD4+ depleting antibody. Compared to control mice, OVA treatment induced IL-17 expression. Moreover, anti-IL-17 antibody markedly reduced OVA-mediated ocular inflammation. Finally, the neutralization of IL-17 attenuated ocular expression of CXCL2 and CXCL5, two cytokines which are chemotactic for neutrophils. Our study suggests that IL-17 is implicated in the pathogenesis of this T cell-mediated model of uveitis in part through neutrophil chemotaxis as a downstream effect of IL-17.

180: Rheumatology international, 2009 Feb 27,
Expression of IL-23 and IL-17 and effect of IL-23 on IL-17 production in ankylosing spondylitis.

[Abstract]The objective of this study was to investigate the expression of IL-23 and IL-17 and the influence of IL-23 on IL-17 production in ankylosing spondylitis (AS) patients. IL-23 and IL-17 levels in the serum and supernatants of cultured peripheral blood mononuclear cells (PBMCs) were determined by ELISA. IL-23p19 mRNA expression in PBMCs were analyzed using RT-PCR. The patients with AS at active stage showed elevated levels of IL-23 and IL-17 in the serum and supernatants of cultured PBMCs. A higher expression of IL-23p19 mRNA in PBMCs of AS patients was also observed. A significantly enhanced production of IL-17 in the supernatants of cultured PBMCs was found in the presence of recombinant IL-23 and this effect was more significant in patients with AS. The results suggest that IL-23 and IL-17 may play critical roles in the pathogenesis of AS and IL-23-stimulated production of IL-17 by PBMCs may be responsible for the development of AS.

181: Science signaling, 2009, 2(59)
IL-17 Receptor Signaling Inhibits C/EBP{beta} by Sequential Phosphorylation of the Regulatory 2 Domain.

[Abstract]Interleukin-17 (IL-17), the hallmark cytokine of T helper 17 (T(H)17) cells, signals through a distinct receptor subclass, yet little is known about the mechanisms involved. IL-17 activates the expression of target genes through the actions of the transcription factors nuclear factor kappaB (NF-kappaB), CAAT enhancer binding protein delta (C/EBPdelta), and C/EBPbeta. The adaptor proteins tumor necrosis factor receptor-associated factor 6 (TRAF6) and Act1 are upstream of NF-kappaB and C/EBPdelta, but the regulation of C/EBPbeta remains undefined. Here, we show that IL-17 signaling led to phosphorylation of two sites in the regulatory 2 domain of C/EBPbeta in a sequential, interdependent fashion. The first was rapid and dependent on extracellular signal-regulated kinase (ERK), whereas the second was dependent on the activity of glycogen synthase kinase 3beta (GSK-3beta). These pathways were mediated by distinct subdomains within IL-17 receptor A (IL-17RA). Whereas phosphorylation of threonine 188 (Thr(188)) was mediated by the previously identified SEF/IL-17R homology domain-Toll-IL-1R-like loop (SEFIR-TILL), phosphorylation of Thr(179) occurred through a newly characterized motif located in the distal tail of IL-17RA. Phosphorylated C/EBPbeta mediated a negative signal, because blocking ERK and GSK-3beta increased expression of IL-17 target genes and a C/EBPbeta-Thr(188) mutant enhanced activation of a C/EBP-dependent reporter. Overexpression of GSK-3beta inhibited IL-17-induced activation of a C/EBP-dependent reporter, and Thr(179) of C/EBPbeta was not phosphorylated in GSK-3beta-deficient cells. Thus, IL-17 triggered the dual phosphorylation of C/EBPbeta, which inhibited the expression of proinflammatory genes. This detailed dissection is the first for the IL-17-mediated C/EBP pathway and the first known example of a negative signal mediated by IL-17RA.

182: Mucosal immunology, 2009 Feb 25, 2(59)
IL-17 disrupts corneal barrier following desiccating stress.

[Abstract]T helper (Th)-17 is a recently identified subtype of Th response that has been implicated in host defense and autoimmunity. We investigated whether there is evidence for a Th-17 response in human and experimental murine dry eye (DE). Gene expression in the human DE conjunctiva showed increased levels of the Th-17 inducers, interleukin (IL)-23, IL-17A, and interferon-gamma (IFN-gamma). In the murine model, we found that desiccating stress increased matrix metalloproteinase-9, Th-17-associated genes (IL-6, IL-23, transforming growth factor-beta1 and -2, IL-23R, IL-17R, IL-17A, retinoid-related orphan receptor-gammat, and CC chemokine attractant ligand-20) and IFN-gamma in cornea and conjunctiva. Furthermore, we found a significantly increased concentration of IL-17 in tears and number of IL-17-producing cells on the ocular surface. Antibody neutralization of IL-17 ameliorated experimental DE-induced corneal epithelial barrier dysfunction and decreased the expression of matrix metalloproteinases 3 and 9. Taken together, these findings suggest that IL-17 has a role in corneal epithelial barrier disruption in DE.Mucosal Immunology advance online publication 25 February 2009. doi:10.1038/mi.2009.5.

183: PLoS ONE, 2009, 4(2)
Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP.

[Abstract]BACKGROUND: Sleep restriction, leading to deprivation of sleep, is common in modern 24-h societies and is associated with the development of health problems including cardiovascular diseases. Our objective was to investigate the immunological effects of prolonged sleep restriction and subsequent recovery sleep, by simulating a working week and following recovery weekend in a laboratory environment. METHODS AND FINDINGS: After 2 baseline nights of 8 hours time in bed (TIB), 13 healthy young men had only 4 hours TIB per night for 5 nights, followed by 2 recovery nights with 8 hours TIB. 6 control subjects had 8 hours TIB per night throughout the experiment. Heart rate, blood pressure, salivary cortisol and serum C-reactive protein (CRP) were measured after the baseline (BL), sleep restriction (SR) and recovery (REC) period. Peripheral blood mononuclear cells (PBMC) were collected at these time points, counted and stimulated with PHA. Cell proliferation was analyzed by thymidine incorporation and cytokine production by ELISA and RT-PCR. CRP was increased after SR (145% of BL; p<0.05), and continued to increase after REC (231% of BL; p<0.05). Heart rate was increased after REC (108% of BL; p<0.05). The amount of circulating NK-cells decreased (65% of BL; p<0.005) and the amount of B-cells increased (121% of BL; p<0.005) after SR, but these cell numbers recovered almost completely during REC. Proliferation of stimulated PBMC increased after SR (233% of BL; p<0.05), accompanied by increased production of IL-1beta (137% of BL; p<0.05), IL-6 (163% of BL; p<0.05) and IL-17 (138% of BL; p<0.05) at mRNA level. After REC, IL-17 was still increased at the protein level (119% of BL; p<0.05). CONCLUSIONS: 5 nights of sleep restriction increased lymphocyte activation and the production of proinflammatory cytokines including IL-1beta IL-6 and IL-17; they remained elevated after 2 nights of recovery sleep, accompanied by increased heart rate and serum CRP, 2 important risk factors for cardiovascular diseases. Therefore, long-term sleep restriction may lead to persistent changes in the immune system and the increased production of IL-17 together with CRP may increase the risk of developing cardiovascular diseases.

184: Neoplasma, 2009, 56(2)
IL-17 family cytokines in neutrophils of patients with oral epithelial squamous cell carcinoma.

[Abstract]Epithelial squamous cell carcinoma is the predominant histological type among cancers of the head and neck. It is characterised by high growth dynamics and a low survival rate of patients. The usefulness of various markers and prognostic factors is assessed to improve treatment results in patients with epithelial squamous cell carcinoma.

The involvement of neutrophils (PMNs) in the neoplastic process and scarce evidence for the role of interleukin 17 (IL-17) family cytokines in these reactions encouraged us to undertake a study in this field. We assessed the expression and capability of neutrophils in patients with oral epithelial squamous cell carcinoma to release IL-17E and IL-17A in relation to their serum levels and expression of the specific receptors, i.e. IL-17R and IL-17BR. For the sake of comparison, the expressions of the proteins examined were assessed in autologous peripheral blood mononuclear cells (PBMCs). The levels were determined in the patients prior to treatment, taking into consideration the stage of the disease according to TNM classification.

Western blot analysis revealed no differences in the expressions of IL-17E and IL-17A either in PMNs or PBMCs of the patients as compared to the healthy subjects. However, the expressions of IL-17BR and IL-17R were found to be higher in both groups of cells in cancer patients as compared to the control. The use of ELISA method revealed that the levels of IL-17E and IL-17A were higher in cell supernatants and blood serum of the patients than of the healthy subjects. No differences were noted in the protein expression in the cells or concentration in supernatants of the patients with different stages of the disease.

Our findings as well as observations reported by other authors seem to indicate some new aspects of the biological role of IL-17 family cytokines, not only as markers of the inflammatory process but also as indicators of leukocyte activity in IL-17A and IL-17E-dependent reactions in patients with oral epithelial squamous cell carcinoma.

Keywords: IL-17, neutrophils, oral epithelial squamous cell carcinoma.

185: Journal of immunotherapy (Hagerstown, Md. : 1997), 2009 Feb-Mar, 32(2)
IL-17 secreted by tumor reactive T cells induces IL-8 release by human renal cancer cells.

[Abstract]TH17 is a newly identified pathogenic memory CD4 T-cell lineage with potent agonist effects in some murine experimental autoimmunity models, however, its role in tumor immunology is still unclear. Clinical experience with interleukin (IL)-2 and ipilumumab [anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody], particularly in treating immunogenic malignancies such as melanoma and renal cell carcinoma (RCC), has suggested an association between a variety of autoimmune phenomena and tumor regression. To investigate this issue in patients with RCC, we isolated T-cell clones from peripheral blood that released IL-17 on stimulation with their autologous RCC tumor line. Clones were generated from 1 patient before any systemic treatment by in vitro stimulation with dendritic cells, autologous tumor, and IL-2 in the presence of anti-CTLA4 antibody. That patient subsequently received treatment with ipilimumab and showed both objective tumor regression and immune-mediated colitis. Limiting dilution cloning of his tumor-dendritic cell-stimulated T cells produced the 3G8D CD4+ clone, which secreted both IL-17 and interferon-gamma when cocultured with the autologous RCC line (transduced with class II transactivation molecule to induce major histocompatibility complex-class II expression). Broader analysis of its cytokine secretion profile showed large amounts of IL-8 when cocultured with RCC, but not when triggered with phorbol 12-myristate 13-acetate and ionomycin. This led to the discovery that IL-8 was being produced by the RCC cells in response to T-cell-derived IL-17. This effect of exogenous IL-17 on IL-8 release from tumor was seen in 5 of 8 RCCs, but not in other tumors tested. Preliminary data on the frequency of IL-17-secreting T cells in the lymphocytes infiltrating RCCs suggest that there may be a positive correlation between this frequency and IL-8 production by nonlymphoid cells as determined by quantitative reverse transcription-polymerase chain reaction. This report extends the known bidirectional interactions between immune cells and malignant cells in the tumor microenvironment that can shape and modulate the host immune response to cancer.

186: Seminars in arthritis and rheumatism, 2010 Apr, 39(5)
Wnt Pathway and IL-17: Novel Regulators of Joint Remodeling in Rheumatic Diseases. Looking Beyond the RANK-RANKL-OPG Axis.

[Abstract]OBJECTIVES: During the last decade research has focused on the RANK-RANKL-OPG (Receptor Activator of Nuclear factor KappaB-Receptor Activator of Nuclear factor KappaB Ligand-Osteoprotegerin) pathway that is currently considered the final common route to bone and joint remodeling. The potential role of novel additional mediators has been highlighted by several reports. This review focuses on the recent information about the pathophysiology of the Wingless (Wnt) pathway and interleukin-17 (IL-17) in relation of their role in bone and joint remodeling. METHODS: An extensive internet search was performed (PubMed) from 1998 and onward using the following keywords: Wnt, bone remodeling, bone, rheumatic diseases, rheumatoid arthritis, IL-17, Th17, osteoblastogenesis, and osteoclastogenesis. RESULTS: Several members of the Wnt pathway play an important role in bone remodeling. Recent experimental data indicate a key role for Dickkopf-1, a soluble inhibitor of the Wnt pathway, in bone remodeling. Increased Dickkopf-1 levels are linked to bone resorption and decreased levels to new bone formation. Low-density lipoprotein receptor-related protein-5, the main receptor that mediates Wnt signaling, plays a critical role in bone mass regulation. Gain-of-function mutations of lipoprotein receptor-related protein-5 cause high bone mass phenotypes, whereas loss-of-function mutations are linked to severe osteoporosis. IL-17 is a proinflammatory cytokine that is produced by a recently described T-cell subset, known as Th17 cells. Evidence suggests that IL-17 is a critical mediator of joint destruction in animal models of arthritis. IL-17 blockade has beneficial effects on murine arthritis, a fact that points to the direction of this cytokine as a potential therapeutic target in human inflammatory arthritides as well. CONCLUSIONS: The available data suggest that mediators in these 2 biologic systems are critical in joint remodeling and may be appropriate targets in the treatment of bone and joint abnormalities that characterize a variety of inflammatory arthritides and bone diseases.

187: Annals of the rheumatic diseases, 2009 Oct, 68(10)
Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway.

[Abstract]OBJECTIVE: To study the effects of different disease-modifying antirheumatic drugs (DMARD) on different events mediated by IL-15-activated lymphocytes. METHODS: Peripheral blood lymphocytes (PBL) were isolated from healthy donors and activated with IL-15 after exposure to different DMARD: leflunomide, cyclosporin A, methotrexate, mycophenolic acid, FK-506, sulphasalazine and sodium aurothiomalate. The expression of different surface molecules on the PBL was then determined by flow cytometry. Cells were also co-cultured with the monocytic cell line THP-1 and the tumour necrosis factor (TNF) concentration in the supernatant was measured after 24 h using an immunoenzyme assay. The effect of the aforementioned drugs on IL-17 production by IL-15-activated PBL was also studied. RESULTS: Treatment of PBL with leflunomide, cyclosporin A and FK-506 inhibited the IL-15-induced expression of both CD54 and CD69 by PBL, as well as TNF production in co-cultures of activated PBL and THP-1 cells. The downregulation of CD54 and CD69 in PBL was correlated with the inhibition of TNF production. Likewise, leflunomide, cyclosporin A and FK-506 all inhibited IL-17 production in IL-15-activated PBL. Interestingly, the effect of leflunomide was not reverted by the presence of uridine in the medium. In addition, leflunomide inhibited the phosphorylation of STAT6 in vitro. CONCLUSION: Inhibition of the JAK/STAT pathway may represent an additional effect of leflunomide in chronic polyarthritis because it impairs certain events that control proinflammatory TNF and IL-17 cytokine production.


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