interleukin 18

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 18

LATEST LITERATURE

1: Journal of neuroimmunology, 2010 Aug 28, 76(3)
Interleukin-18 deficiency reduces neuropeptide gene expressions in the mouse amygdala related with behavioral change.

[Abstract]In this study, we examined the effects of IL-18 deficiency on behaviors and gene expression profiles in 6 brain regions. IL-18(-/-) mice reduced depressive-like behavior and changed gene expressions predominantly in the amygdala compared with wild-type mice. Pathway analysis of the differentially expressed genes ranked behavior as the top-scored biological function. Of note, the absence of IL-18 decreased Avp, Hcrt, Oxt, and Pmch mRNA levels and the number of arginine vasopressin- and oxytocin-positive cells in the amygdala, but not in the hypothalamus. Our results suggest that IL-18-dependent vasopressinergic and oxytocinergic circuitry in the amygdala may regulate depressive-like behaviors in mice.

2: Fertility and sterility, 2010 Aug 25, 76(3)
Functional association of interleukin-18 gene -607 C/A promoter polymorphisms with endometriosis.

[Abstract]This study evaluated for the first time the relationship between interleukin-18 (IL-18) C607A genotypes and endometriosis in 135 women with endometriosis and 84 controls. In the study population, IL-18 -607 *A homozygote and A allele were positively correlated with the risk of developing endometriosis or the stage of endometriosis.

3: The American surgeon, 2010 Aug, 76(8)
Combined analysis of allograft inflammatory factor-1, interleukin-18, and Toll-like receptor expression and association with allograft rejection and coronary vasculopathy.

[Abstract]In cardiac transplantation settings, the initial myocardial ischemia and reperfusion may cause myocyte tissue injury and the release of allograft inflammatory factor-1 (AIF-1). This in part may trigger the innate immune response through the modulation of Toll-like receptor-2 (TLR-2) and AIF-1 expression and function, causing the release of proinflammatory cytokines. The goal was to demonstrate these markers in the peripheral blood and biopsy specimen from recipients with cardiac allograft rejection and coronary vasculopathy (CV). Peripheral blood and endomyocardial specimens were tested by reverse transcriptase-polymerase chain reaction and immunohistochemistry stains for identification of TLR-2, -4, interleukin-18, and AIF-1 markers and analyzed against clinical rejection grades for rejection. The differences for mRNA transcript levels were determined by one-way analysis of variance. The mRNA expression levels were significantly varied for TLR-2 in monocytes with different rejection grades (P < 0.0001). The mean +/- SEM level of mRNA expression for 3A grade rejection was 64.21 +/- 3.8; grade 1A, 38.4 +/- 3.5; and for Grade 0 was 38.46 +/- 2.8. The TLR-4 mRNA expression was increased but the specificity was not statistically significant. The TLR-2 immunoreactivity was strongly detected in infiltrating mononuclear cells and cardiac myocytes in Grade 3A rejection. AIF-1 expression was increased significantly in the group with 3A rejection and Grade III CV as compared with Grade 0 or 1A. Interleukin-18 receptors were strongly detected in Grade 3A rejection and CV. The expression profiles of AIF-1, TLR-2, and interleukin-18 were correlated with biopsy-proven allograft rejection in both peripheral blood and local tissue, suggesting a potential for diagnostic biomarkers for early detection of allograft rejection.

4: Medical oncology (Northwood, London, England), 2010 Aug 20, 76(3)
Significance of vascular endothelial growth factor, interleukin-18 and nitric oxide in patients with breast cancer: correlation with carbohydrate antigen 15.3.

[Abstract]The aim of this study was to determine serum concentrations of angiogenic factors including vascular endothelial growth factor (VEGF), interleukin 18 (IL-18) and nitric oxide (NO) in patients with breast cancer and to evaluate whether these factors will be correlated with CA 15.3, as a routine tumor marker for breast cancer or not. This study was conducted on 44 patients with breast cancer and 15 healthy individuals as a control group. The results demonstrated significant increase in serum IL-18, NO and CA 15.3 levels in sera of breast cancer patients when compared to those of the control group (P < 0.001, P = 0.016 and P < 0.001, respectively). However, the mean serum level of VEGF in patients as showed insignificant increase compared to that of the controls was not significant (P = 0.311). Sensitivity of CA 15.3, VEGF, IL-18 and NO to detect patients with disease was 52.2, 21.3, 77.2 and 70.4 %, respectively. In addition, positive status of serum CA 15.3 and/or IL-18 was found in 39 out of 44 (88.6 %) patients, and the positive status of serum CA 15.3 and/or NO was only found in 35 out of 44 (79.5 %). In conclusion, the simultaneous determination of IL-18 or NO in combination with the CA 15.3 may increase the sensitivity to diagnose breast cancer and may aid in disease prognosis.

5: Current medicinal chemistry, 2010 Aug 16, 76(3)
Interleukin-18: Biology and Role in the Immunotherapy of Cancer.

[Abstract]Interleukin-18 (IL-18) is an immunostimulatory cytokine belonging to the IL-1 family. IL-18 can regulate both innate and adaptive immune responses through its effects on natural killer (NK) cells, monocytes, dendritic cells, T cells, and B cells. IL-18 acts synergistically with other pro-inflammatory cytokines to promote interferon-gamma (IFN-gamma) production by NK cells, T cells, and possibly other cell types. Systemic administration of IL-18 has been shown to have significant antitumor activity in several preclinical animal models. Phase I clinical trials of recombinant human IL-18 have demonstrated that it can be safely administered to patients with advanced cancer. Biologic effects of IL-18 therapy include activation of monocytes, NK cells, and T cells and production of IFN-gamma as well as other cytokines in vivo. A phase II study of IL-18 in patients with metastatic melanoma confirmed its safety but suggested limited efficacy of IL-18 monotherapy in this setting. IL-18 appears to act predominantly as a costimulatory cytokine and its optimal use for cancer immunotherapy may be in combination with other immunostimulatory cytokines, vaccines, or monoclonal antibodies.

6: American journal of physiology. Heart and circulatory physiology, 2010 Aug 6, 136(3-4)
Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Sp1 signaling, and MMP9 in part via EMMPRIN, and through AP-1 and NF-{kappa}B activation.

[Abstract]Interleukin (IL)-18 and the extracellular matrix metalloproteinase inducer (EMMPRIN) stimulate the expression of proinflammatory cytokines and matrix metalloproteinases, and are elevated in myocardial hypertrophy, remodeling, and failure. Here we report several novel findings in primary cardiomyocytes treated with IL-18; (i) IL-18 activates multiple transcription factors including nuclear factor (NF)-kappaB (p50, p65), activator protein (AP)-1 (cFos, cJun, JunD), GATA, CCAAT enhancer binding protein, myocyte-specific enhancer-binding factor, interferon regulatory factor 1 (IRF-1), p53, and specific protein-1 (Sp1). (ii) IL-18 induces EMMPRIN expression via MyD88/IRAK/TRAF6/JNK-dependent Sp1 activation. (iii) IL-18 induces a number of MMP genes, particularly MMP9, at a rapid rate, as well as the inhibitors TIMPs 1 and 3 at a slower rate. (iv) IL-18 induction of MMP9 is mediated in part via EMMPRIN, and through JNK- and ERK-dependent AP-1 activation and p38MAPK-dependent NF-kappaB activation. These results suggest that the elevated expression of IL-18 during myocardial injury and inflammation may favor EMMPRIN and MMP induction, and ECM degradation. Therefore targeting IL-18 or its signaling pathways may be of potential therapeutic benefit in adverse remodeling.

7: Veterinary immunology and immunopathology, 2010 Jul 16, 116(4)
Characterization of monoclonal antibodies against goat interleukin-18 and their application in the measurement of goat interleukin-18 in LPS-stimulated peripheral blood mononuclear cells by sandwich ELISA.

[Abstract]In order to develop a specific assay for the measurement of goat IL-18 level, two stable hybridoma cell lines were established which secreted IgG1 monoclonal antibodies (mAbs) against goat IL-18. Specific binding of two mAbs named 2E8 and 4C4 to recombinant goat IL-18 expressed in Escherichia coli was demonstrated in an ELISA and Western blotting. Results also showed that mAbs 2E8 and 4C4 bound to distinct epitopes in the ELISA additivity test. These two mAbs were applied in IFA analysis for the detection of goat IL-18 expressed in 293FT cells and in the sandwich ELISA for the measurement of goat IL-18 levels in LPS-stimulated PBMC. Results from this study demonstrated that mAbs against goat IL-18 recognize bovine and human IL-18 and could be used to measure IL-18 levels in different inflammations or immune responses in future studies.

8: Arteriosclerosis, thrombosis, and vascular biology, 2010 Aug 5, 136(3-4)
Interleukin-18 as a Predictor of Future Events in Patients With Acute Coronary Syndromes.

[Abstract]OBJECTIVE: The aim of this study was to assess the short- and long-term prognostic significance of interleukin-18 (IL-18) levels in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: In patients hospitalized with ACS (median age, 66 years; 30% females), we evaluated associations of serum IL-18 levels from day 1 (n=1261) with the short- (<3 months) and long-term (median, 7.6 years) risk of death, development of congestive heart failure (CHF), and myocardial infarction (MI). IL-18 was not significantly associated with short-term mortality. In the long term, IL-18 levels were significantly related to all-cause mortality, even after adjustment for clinical confounders (hazard ratio [HR], 1.19; 95% confidence interval, 1.07 to 1.33; P=0.002). Long-term, cardiovascular mortality was univariately related to IL-18, and the adjusted relation between noncardiovascular mortality and IL-18 was highly significant (HR, 1.36; 95% confidence interval, 1.11 to 1.67; P=0.003). IL-18 independently predicted CHF, MI, and cardiovascular death/CHF/MI in both the short and long term. Measurements from day 1 of ACS and 3 months after ACS had a similar power to predict late outcome. CONCLUSIONS: The addition of the measurement of IL-18 to clinical variables improved the prediction of risk of all-cause and noncardiovascular mortality. The association between IL-18 and noncardiovascular mortality is intriguing and warrants further study.

9: Annals of the rheumatic diseases, 2010 Aug 2, 136(3-4)
Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases.

[Abstract]BACKGROUND: /st> Interleukin 18 (IL-18) is a novel mediator of angiogenesis in rheumatoid arthritis (RA). OBJECTIVE: /st> To examine the role of IL-18 in RA angiogenesis and the signalling mechanisms involved. METHODS: /st> Human dermal microvascular endothelial cell (HMVEC) chemotaxis, capillary morphogenesis assays and Matrigel plug angiogenesis assays were performed in vivo using IL-18 with or without signalling inhibitors. A novel model of angiogenesis was devised using dye-tagged HMVECs to study their homing into RA and normal (NL) synovial tissues (STs) engrafted in severe combined immunodeficient (SCID) mice. RESULTS: /st> IL-18-mediated angiogenesis depended on Src and Jnk, as the inhibitors of Src and Jnk blocked IL-18-induced HMVEC chemotaxis, tube formation and angiogenesis in Matrigel plugs. However, inhibitors of Janus kinase 2, p38, MEK, phosphatidylinositol-3-kinase and neutralising antibodies to vascular endothelial growth factor or stromal derived factor-1alpha did not alter IL-18-induced HMVEC migration. These results were confirmed with Jnk or Src sense or antisense oligodeoxynucleotides. Moreover, IL-18 induced phosphorylation of Src and Jnk in HMVECs. As proof of principle, IL-18 null mice had a significantly decreased angiogenesis compared with wild-type mice in Matrigel plug angiogenesis assays in vivo. IL-18 markedly enhanced mature HMVEC homing to human RA ST compared with NL ST in SCID mice, confirming the role of IL-18-induced angiogenesis in RA ST in vivo. CONCLUSION: /st> Targeting IL-18 or its signalling intermediates may prove to be a potentially novel therapeutic strategy for angiogenesis-dependent diseases, such as RA.

10: Veterinary immunology and immunopathology, 2010 Jul 6, 116(4)
Development and characterization of mouse monoclonal antibodies specific for chicken interleukin 18.

[Abstract]Four mouse monoclonal antibodies (mAbs) which are specific for chicken interleukin 18 (chIL18) were produced and characterized by enzyme-linked immunosorbent assay (ELISA), Western blotting, quantitative real-time PCR and neutralization assays. Using Western blot analysis, monoclonal antibodies specific for chIL18 identified a 23kDa Pichia pastoris-expressed chIL18 and 66kDa E. coli-derived MBP fusion protein of chIL18. Bioassays for chIL18 using primary chicken spleen cells showed dose-dependent IFN-gamma mRNA expression and induction of IFN-gamma from primary splenocytes, and triggered nitric oxide (NO) production in the HD11 macrophage cell line. These mAbs showed neutralizing chIL18 activity. Taken together, these mouse mAbs which detect chicken IL-18 will be significant new immune reagents and useful tools for basic and applied research in poultry.

11: Neuroscience, 2010 Jul 29, 76(2)
The Protective Effects of Interleukin-18 and Interferon-gamma on Neuronal Damages in the Rat Hippocampus Following Status Epilepticus.

[Abstract]To elucidate whether interleukin-18 (IL-18) or interferon-gamma (IFN-gamma) participates in neurodegeneartion, we investigated the changes in IL-18 and INF-gamma systems within the rat hippocampus following status epilepticus (SE). In non-SE induced animals, IL-18, IL-18 receptor alpha (IL-18Ralpha), IFN-gamma and IFN-gamma receptor alpha (IFN-gammaRalpha) immunoreactivity was not detected in the hippocampus. Following SE, IL-18 immunoreactivity was increased in CA1-3 pyramidal cells as well as dentate granule cells. IL-18 immunoreactivity was also up-regulated in astrocytes and microglia/macrophages. IL-18Ralpha immunoreactivity was detected in astrocytes and microglia/macrophages. IFN-gamma immunoreactivity was detected only in astrocytes within all regions of the hippocampus. IFN-gammaRalpha immunoreactivity was increased in neurons as well as astrocytes. Intracerebroventricular infusions of recombinant rat IL-18 or INF-gamma alleviated SE-induced neuronal damages, while neutralization of IL-18, INF-gamma or their receptors aggravated them, as compared to saline-infused animals. These findings suggest that astroglial-mediated INF-gamma pathway in response to IL-18 induction may play an important role in alleviation of SE-induced neuronal damages.

12: Scandinavian journal of clinical and laboratory investigation, 2010 Jul 23, 89(1)
The association between interleukin-18 and pulmonary sarcoidosis: A meta-analysis.

[Abstract]Abstract Objective. To assess the association between interleukin-18 (IL-18) and pulmonary sarcoidosis. Materials and methods. The Medline, Embase and Cochrane databases were searched to identify relevant studies. Studies were eligible for inclusion if they enrolled newly-diagnosed, untreated pulmonary sarcoidosis patients with IL-18 measurement in bronchoalveolar lavage fluid (BALF) or blood. A randomized effects model was used to pool six relevant studies. Results. The IL-18 levels of BALF and blood in patients with pulmonary sarcoidosis were significantly higher than those in control subjects (p = 0.0001, p = 0.04, respectively). Conclusion. This meta-analysis has observed some evidence showing that the published results from these studies indicated the statistically significant association between IL-18 and pulmonary sarcoidosis.

13: Journal of dermatological science, 2010 Jun 17, 30(4)
Granzyme B is a novel interleukin-18 converting enzyme.

[Abstract]BACKGROUND: Granzyme B (GrB) is recognized to induce apoptosis; however, little is known about its possible role in other biological events. IL-18, a potent inflammatory cytokine, is produced as an inactive precursor (proIL-18). Several cells, including monocytes/macrophage lineage and non-hematopoietic cells such as keratinocytes, produce proIL-18. ProIL-18 requires appropriate processing to become active. Caspase-1 is the authentic IL-18 processing enzyme and is essential for IL-18 release from monocyte/macrophage lineage cells. However, caspase-1 is absent in non-hematopoietic cells, suggesting that there is another candidate to cleave proIL-18 except for caspase-1. OBJECTIVE: GrB can invade and be active in cytoplasm of non-hematopoietic cells via perforin, therefore we investigated whether GrB converts proIL-18 into the biologically active form. METHODS: Recombinant proIL-18 (rproIL-18) was produced and purified for protease reaction with GrB; this incubate was evaluated by immunoblotting. Biological activity of the proteolytic fragment cleaved by GrB was determined by IFN-gamma assay using KG-1 cells. IFN-gamma induction was also analyzed between extracts from GrB(+)/caspase-1(-) human CD8+ T cells and proIL-18 from normal human keratinocytes (NHK). RESULTS: The proteolytic fragment that GrB cleaved proIL-18 had the same sequence and biological activity compared with mature IL-18 cleaved by caspase-1. Culture extracts from CD8+ T cells was able to cleave proIL-18 into authentic mature IL-18. IFN-gamma induction was also detected in NHK treated with CD8+ T cells. CONCLUSION: GrB is a potent IL-18 converting enzyme and suggest that GrB secreted by CTLs and/or NK cells may initiate IL-18 release from target cells, leading to the development of inflammation.

14: Menopause (New York, N.Y.), 2010 Jul 2, 89(1)
Effects of raloxifene on serum macrophage colony-stimulating factor and interleukin-18 levels in postmenopausal women younger than 60 years.

[Abstract]OBJECTIVE:: Macrophage colony-stimulating factor (M-CSF) and interleukin-18 (IL-18) are cytokines expressed predominantly in atheromatous plaque, and overproduction of these has been found to be associated with coronary artery disease. The aim of this study was to investigate the effect of raloxifene, a selective estrogen receptor modulator, on serum M-CSF and IL-18 levels, cytokines that are presumably involved in the pathogenesis of atherosclerosis. METHODS:: A total of 70 postmenopausal women (age, 56.45 +/- 1.52 y) without previously confirmed cardiovascular disease were enrolled in a 6-month prospective, randomized, controlled study. Women were randomly assigned to two groups: 35 women received oral administration of 60 mg/day raloxifene for 6 months and 35 were in the control group and received no medications. Serum lipid concentrations and high-sensitivity C-reactive protein (hs-CRP), M-CSF, and IL-18 levels were measured at baseline and at the sixth month in both groups. RESULTS:: Compared with the control group, the raloxifene group had a significant decrease in serum IL-18 concentrations and a 25.29% reduction in serum hs-CRP concentrations. M-CSF levels were reduced by 5.94% in the raloxifene group, but the difference was not statistically significant. At the sixth month, 60 mg/day of raloxifene significantly decreased the median serum total cholesterol and low-density lipoprotein cholesterol levels when compared with the baseline levels. CONCLUSIONS:: Raloxifene reduces serum total cholesterol, low-density lipoprotein cholesterol, hs-CRP, and IL-18 levels. According to the results of our study, it is suggested that raloxifene may have a favorable effect on the prevention of cardiovascular disease in healthy postmenopausal women younger than 60 years.

15: Scandinavian journal of clinical and laboratory investigation, 2010 Jul 7, 89(1)
Circulating levels of interleukin-18 in patients with non-alcoholic fatty liver disease.

[Abstract]Abstract Background and aims. Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and diabetes mellitus. IL-18 is associated with obesity and metabolic syndrome. Our aim was to investigate the relationship of IL-18 with adiponectin and liver histology in subjects with NAFLD who had no additional disorder such as morbid obesity, diabetes mellitus and hypertension. Methods. Plasma levels of IL-18 and adiponectin were measured by ELISA in 96 male subjects with NAFLD [n = 65 for non-alcoholic steatohepatitis (NASH) and n = 31 for simple steatosis (SS)]. Results. IL-18 levels were not different between the two groups (p = 0.89). There was no significant association of IL-18 with adiponectin, insulin resistance and histopathological findings. Adiponectin was lower in the NASH group compared to the SS group (p = 0.02) and it was found to be negatively correlated with hepatic steatosis and fibrosis (r = -0.442, p < 0.001 and r = -0.292, p = 0.02, respectively). Conclusions. This study indicates that circulating IL-18 levels are not altered in male subjects with NAFLD. These results suggest that in the absence of metabolic risk factors, IL-18 per se may not be involved in the pathogenesis of NASH and SS.

16: Rheumatology (Oxford, England), 2010 Jul 3, 89(1)
Interleukin-18 is a key mediator in dermatomyositis: potential contribution to development of interstitial lung disease.

[Abstract]Objective. To determine whether IL-18 is involved in the inflammation of DM and PM. Methods. Thirty-three patients with DM were enrolled in this study, including 25 with interstitial lung disease (ILD). In addition, 16 patients with PM were enrolled, including 6 with ILD. All patients were admitted to our hospital as a result of their condition requiring treatment, and clinical laboratory data including serum IL-18 were recorded on admission. Results. Serum IL-18 was significantly (P < 0.0001) higher in both DM and PM patients than in healthy controls (n = 30). Serum ferritin and IL-18 were significantly (P = 0.003 and 0.0044, respectively) higher in DM than in PM patients. Additionally, ferritin and IL-18 were significantly (P = 0.023 and 0.034, respectively) higher in DM patients with ILD than in DM patients without ILD. Significant positive correlations were found between creatine kinase (CK) and ferritin (r(s) = 0.39, P = 0.024); CK and IL-18 (r(s) = 0.48, P = 0.005); and IL-18 and ferritin (r(s) = 0.54, P = 0.0012) in the DM group as a whole. These findings were different for the DM plus ILD subgroup: significant positive correlations were found between CK and ferritin (r(s) = 0.40, P = 0.047); CK and IL-18 (r(s) = 0.63, P = 0.0008); and IL-18 and ferritin (r(s) = 0.41, P = 0.042). Conclusion. Serum IL-18 was strikingly elevated in patients with DM and was associated particularly with disease activity and ILD complication in DM.

17: Arthritis research & therapy, 2010 Jun 16, 12(3)
Interleukin-18 as an in vivo mediator of monocyte recruitment in rodent models of rheumatoid arthritis.

[Abstract]ABSTRACT: INTRODUCTION: The function of interleukin-18 (IL-18) was investigated in pertinent animal models of rodent rheumatoid arthritis (RA) to determine its proinflammatory and monocyte recruitment properties. METHODS: We utilized a modified Boyden chemotaxis system to examine monocyte recruitment to recombinant human (rhu) IL-18 in vitro. Monocyte recruitment to rhuIL-18 was then tested in vivo using an RA synovial tissue (ST) severe combined immunodeficient (SCID) mouse chimera. We defined monocyte specific signal transduction pathways induced by rhuIL-18 by Western blotting analysis, and linked this to in vitro monocyte chemotactic activity. Finally, the ability of IL-18 to induce a cytokine cascade during acute joint inflammatory responses was examined by inducing wild-type (Wt) and IL-18 gene knockout mice with zymosan induced arthritis (ZIA). RESULTS: We found that intragraft injected rhuIL-18 was a robust monocyte recruitment factor to both human ST and regional (inguinal) murine lymph node (LN) tissue. IL-18 gene knockout mice also showed pronounced reductions in joint inflammation during ZIA compared to Wt mice. Many proinflammatory cytokines were reduced in IL-18 gene knockout mouse joint homogenates during ZIA including macrophage inflammatory protein-3alpha (MIP-3alpha/CCL20), vascular endothelial cell growth factor (VEGF) and IL-17. Signal transduction experiments revealed that IL-18 signals through p38 and ERK1/2 in monocytes, and that IL-18 mediated in vitro monocyte chemotaxis can be significantly inhibited by disruption of this pathway. CONCLUSIONS: Our data suggests that IL-18 may be produced in acute inflammatory responses and supports the notion that IL-18 may serve a hierarchal position for initiating joint inflammatory responses.

18: Clinical journal of the American Society of Nephrology : CJASN, 2010 Jun 17, 29(7)
Elevated Urinary IL-18 Levels at the Time of ICU Admission Predict Adverse Clinical Outcomes.

[Abstract]BACKGROUND AND OBJECTIVES: Urine IL-18 (uIL-18) has demonstrated moderate capacity to predict acute kidney injury (AKI) and adverse outcomes in defined settings. Its ability to predict AKI and provide prognostic information in broadly selected, critically ill adults remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study prospectively evaluated the capacity of uIL-18 measured within 24 hours of intensive care unit (ICU) admission to predict AKI, death, and receipt of acute dialysis in a large mixed-adult ICU population. RESULTS: Of 451 patients, 86 developed AKI within 48 hours of enrollment and had higher median uIL-18 levels [426 (interquartile range [IQR]: 152 to 1183) pg/mg creatinine] compared with those without AKI [248 (IQR: 120 to 559) pg/mg]. The area under the receiver operating characteristic curve for uIL-18 predicting subsequent AKI within 24 hours was 0.62 (95% CI: 0.54 to 0.69) and improved modestly to 0.67 (95% CI: 0.53 to 0.81) in patients whose enrollment eGFR was >/=75 ml/min per 1.73 m(2). The highest median uIL-18 levels were observed in patients with sepsis at enrollment [508 (IQR: 230 to 1281) pg/mg], those receiving acute dialysis [571 (IQR: 161 to 1614) pg/mg] or dying [532 (IQR: 210 to 1614) pg/mg] within 28 days of ascertainment. After adjustment for a priori selected clinical predictors, uIL-18 remained independently predictive of composite outcome of death or acute dialysis within 28 days of ascertainment (odds ratio, 1.86 [95% CI: 1.31 to 2.64]). CONCLUSIONS: uIL-18 did not reliably predict AKI development, but did predict poor clinical outcomes in a broadly selected, critically ill adult population.

19: Antiviral research, 2010 May 27, 24(4)
Enhancement of the immunogenicity of an infectious laryngotracheitis virus DNA vaccine by a bicistronic plasmid encoding glycoprotein B and interleukin-18.

[Abstract]A DNA vaccine against infectious laryngotracheitis virus (ILTV) can induce specific humoral and cell-mediated immunity. However, compared to conventional vaccines, DNA vaccines usually induce poor antibody responses. To determine if co-expression of a cytokine can result in a more potent ILTV DNA vaccine, immunogenicity and protective efficacy of a monocistronic vector encoding the glycoprotein B (gB) of ILTV was compared to that of a bicistronic vector separately encoding the gB and chicken interleukin-18. Humoral and cellular responses induced by the DNA vaccines administered to the quadriceps muscle of chickens were evaluated. There were significant differences in antibody levels elicited by either monocistronic or bicistronic DNA vaccines as determined by ELISA. The percentages of CD3(+), CD3(+)CD8(+) and CD3(+)CD4(+) subgroups of peripheral blood T-lymphocytes in chickens immunized with the bicistronic DNA vaccine were higher than those in chickens immunized with monocistronic DNA vaccine. When chickens were challenged with a virulent CG strain of ILTV, the protective efficacy was enhanced significantly after immunization with the bicistronic DNA vaccine. These results demonstrated that co-expression of an adjuvant cytokine from a bicistronic DNA vaccine may be an effective approach to increasing ILTV DNA vaccine immunogenicity.

20: Tissue antigens, 2010 Jun 7, 29(7)
Interleukin-18, transforming growth factor-beta, and vascular endothelial growth factor gene polymorphisms and susceptibility to primary glomerulonephritis.

[Abstract]Several studies have showed an association of gene polymorphisms with the development of glomerulonephritis (GN). We investigated the effects of gene polymorphisms on the development of GN by analyzing polymorphisms in the interleukin (IL)-18, transforming growth factor (TGF)-beta, and vascular endothelial growth factor (VEGF) genes in Korean patients with primary GN. The study included 146 normal subjects (controls) and 100 patients diagnosed with primary GN by kidney biopsy. The gene polymorphisms A-607C and G-137C in IL-18, C-509T and T869C in TGF-beta1, and C-2578A and C405G in VEGF were investigated in DNA extracted from peripheral blood. Significant differences were observed between the GN and control groups in the genotype and allele frequencies of A-607C IL-18 and C405G VEGF. The frequencies of the IL-18-607CC genotype [P = 0.001, odds ratio (OR) = 2.473] and the VEGF 405GG genotype (P = 0.001, OR = 2.473) were significantly increased in the GN group. The combination of IL-18-607CC+ and VEGF 405GG+ genotypes had a higher risk for developing GN in comparison with the combination of IL-18-607CC- and VEGF 405GG- genotypes (P < 0.001, OR = 8.642). In the haplotype analysis of the IL-18 gene, the CG haplotype was significantly more frequent in the GN group than the control group (61.5% vs 46.9%, P = 0.002). These results show that the -607CC genotype of the IL-18 gene and the 405GG genotype of the VEGF gene are associated with susceptibility to and the development of primary GN.

21: Journal of molecular and cellular cardiology, 2010 Jun 7, 29(7)
EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB and MKK7/JNK/AP-1 signaling.

[Abstract]The transmembrane glycoprotein extracellular matrix metalloproteinase inducer (EMMPRIN) and the pleiotropic proinflammatory cytokine interleukin (IL)-18 play critical roles in myocardial remodeling, by inducing matrix degrading metalloproteinases (MMPs). Previously we showed that IL-18 induces EMMPRIN expression in cardiomyocytes via MyD88/IRAK4/TRAF6/JNK-dependent Sp1 activation. Here in reciprocal studies we demonstrate that EMMPRIN is a potent inducer of IL-18 transcription, protein expression and protein secretion in primary mouse cardiomyocytes. We show for the first time that EMMPRIN stimulates the activation of NF-kappaB, AP-1, CREB, and ATF-2 in cardiomyocytes, and induces IL-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB and MKK7/JNK/AP-1 signaling. Moreover, EMMPRIN induces robust time-dependent induction of various MMP mRNA. EMMPRIN also induces the mRNA of TIMPs 1 and 3, but in a delayed fashion. These results suggest that IL-18-induced EMMPRIN expression may favor net MMP expression and ECM destruction, and thus identify both as potential therapeutic targets in countering adverse myocardial remodeling.

22: The Journal of dermatology, 2010 Jun 1, 37(6)
Acute stress enhances contact dermatitis by promoting nuclear factor-kappaB DNA-binding activity and interleukin-18 expression in mice.

[Abstract]Abstract Psychological stress adversely affects the immune system, and aggravates various skin diseases, such as psoriasis, alopecia areata and atopic dermatitis. However, the precise underlying mechanisms remain to be elucidated. The goal of this study was to use a murine restraint stress model to determine the mechanisms by which psychological stress modulates immune response in contact dermatitis. In the present study, mice were sensitized and challenged on the skin with 2,4-dinitrofluorobenzene. Acute restraint stress was administrated to healthy or sensitized mice before challenge, and nuclear factor (NF)-kappaB DNA-binding activation of nuclear protein and expression of interleukin (IL)-18 mRNA in murine spleen lymphocytes was detected. Chemical sympathectomy was performed using the neurotoxin 6-hydroxy-dopamine to determine the effect of the sympathetic nervous system. The experiment showed that restraint stress induced a series of changes which include increasing of NF-kappaB DNA-binding activity and IL-18 mRNA expression in spleen lymphocytes and enhancement of contact hypersensitivity response, and these changes may be mediated by the sympathetic nervous system. These findings provide new insights into the roles of the nervous system in the aggravation of skin diseases.

23: Tissue antigens, 2010 May 30, 24(4)
Association of interleukin 18 gene polymorphism with susceptibility to the development of acute lung injury after cardiopulmonary bypass surgery.

[Abstract]The activation and recruitment of neutrophil cells in lung tissue are the characteristic features of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Interleukin 18 (IL-18) is a potent activator and inducer of accumulating neutrophils in lung, and higher IL-18 level has been shown to link to IL-18 gene -607C/C genotype. Therefore, the polymorphisms in IL-18 gene promoter were examined to investigate the association with susceptibility to the development of ALI after cardiopulmonary bypass (CPB) surgery in this study. The results showed the significant involvement of -607C/ genotype in patients with ALI (n = 18, 18/43, 41.9%) compared with those patients without ALI (n = 32, 32/155, 20.6%, P = 0.0037) and healthy controls (n = 198, 53/198, 26.8%, P = 0.06). The frequencies of -607C/C,C/A,A/A genotypes were 41.9%, 46.5%, and 11.6% in patients with ALI and 20.6%, 47.1%, and 32.3% in patients without ALI. The allelic frequency of C (65.1%) was significantly higher in patients with ALI than that of patients without ALI (44.2%) [odds ratio(OR) = 0.42, 95% confidence interval (CI) = 0.26 - 0.70; P = 0.0006]. No significant association of -137 polymorphism with susceptibility of ALI was found. There were no significant differences between the patients who had undergone CPB operation and healthy controls. In conclusion, our findings suggest that -607C/C genotype in IL-18 gene plays a pivotal role in the development of ALI after CPB surgery in Chinese Han population.

24: International immunology, 2010 May 23, 24(4)
Contribution of IL-18 to eosinophilic airway inflammation induced by immunization and challenge with Staphylococcus aureus proteins.

[Abstract]We previously reported that intranasal challenge with ovalbumin (OVA) plus IL-18 induces airway hyperresponsiveness (AHR) and eosinophilic airway inflammation in mice with OVA-specific T(h)1 cells. These two conditions can be prevented by neutralizing anti-IFN-gamma and anti-IL-13 antibodies, respectively. The mice develop AHR and eosinophilic airway inflammation after challenge with OVA plus LPS instead of IL-18 and endogenous IL-18 is known to be involved. In contrast, IL-18 does not facilitate these changes in mice possessing OVA-specific T(h)2 cells. Here, we investigated whether IL-18 is involved in the development of asthma in mice immunized and challenged with bacterial proteins. Upon intranasal exposure to protein A (SpA) derived from Staphylococcus aureus, mice immunized with SpA exhibited AHR and peribronchial eosinophilic inflammation if IFN-gamma or IL-13 were present, respectively. The CD4(+) T cells from draining lymph nodes (DLNs) of the SpA-immunized and -challenged mice produced a robust IFN-gamma and IL-13 in response to immobilized anti-CD3 antibodies. Treatment with neutralizing anti-IL-18 antibodies prevented asthmatic inflammation concomitant with their impaired potential to express IFN-gamma and IL-13. Furthermore, naive mice that received the CD4(+) T cells from DLNs of SpA-immunized mice developed airway inflammation depending upon the presence of IL-18. Immunodeficient mice that received human PBMCs, which had been stimulated with SpA in vitro, developed dense peribronchial accumulation of human CD4(+) T cells upon SpA challenge. Neutralizing anti-human IL-18 antibodies protected against this airway inflammation. These results suggest the importance of IL-18 for the development of asthmatic inflammation associated with airway exposure to bacterial proteins.

25: Neurological research, 2010 May, 32(4)
The serum interleukin-18 is a potential marker for development of post-stroke depression.

[Abstract]OBJECTIVE: Depression is a common mood disorder affecting stroke patients. It is associated with poorer outcome and increased mortality in stroke patients. The aim of this work was to test whether serum levels of proinflammatory cytokines are correlated with the development of depression after stroke. METHODS: One hundred ischemic stroke patients admitted to the hospital within the first 24 hours after stroke onset were consecutively recruited and followed up for 6 months. The 17-item Hamilton Depression Rating Scale (HDRS) and Montgomery-Asberg Depression Rating Scale (MADRS) were used to screen for depressive symptoms on days 3, 7 and 14 after admission and at 6 months after stroke onset. Based on the symptoms elicited from these two scales, diagnoses of depression were made in accordance with DSM-IV criteria for post-stroke depression. Serum levels of proinflammatory cytokines (IL-6, IL-18 and TNF-alpha) of all the patients were determined by ELISA on both days 1 and 7 after admission. Meanwhile, 50 healthy control subjects were also recruited; they underwent measurement of serum levels of proinflammatory cytokines once. RESULTS: Thirty-seven patients (37.0%) were diagnosed as having major depression at 2 weeks. Serum IL-18 on both days 1 and 7 was significantly higher in both post-stroke depression patients and non-post-stroke depression patients than in normal controls. Serum IL-18 on day 7 was significantly higher in post-stroke depression patients than in non-post-stroke depression patients. Serum IL-18 >377.84 pg/ml on day 7 was independently associated with incident post-stroke depression at the acute stage of stroke (odds ratio: 12.280, 95% confidence interval: 3.848-39.190, p<0.001 after adjustment). At 6 months, 31 patients (33.0%) were diagnosed with major depression. Serum IL-18 >376.67 pg/ml on day 7 was independently associated with post-stroke depression at 6 months (odds ratio: 7.431, 95% confidence interval: 1.741-31.712, p=0.007 after adjustment). CONCLUSIONS: Serum IL-18 on day 7 after admission may predict the risk of post-stroke depression both at the acute stage of stroke and at 6 months post-stroke.

26: Journal of periodontology, 2010 May 17, 24(4)
Periodontal Disease in Association with Systemic Levels of Interleukin-18 and CXC Ligand 16 in Patients Undergoing Cardiac Catheterization.

[Abstract]Background: Interleukin-18 (IL-18) is a pro-inflammatory cytokine present in chronically inflamed tissues; it has been positively associated with both periodontitis and coronary artery disease (CAD). CXC ligand 16 (CXCL16), a recently discovered chemokine, has been identified in atherosclerotic lesions; its role in periodontal diseases is largely unknown. The primary aim of this research study was to correlate periodontal parameters with systemic levels of IL-18 and CXCL16. Methods: Fifty-one patients presenting for clinically indicated coronary angiography received full mouth periodontal examinations. Periodontal status was defined using frequency distributions of probing depth (PD), clinical attachment loss (CAL), and bleeding on probing (BOP). Blood samples were collected during cardiac catheterization and plasma levels of IL-18 and CXCL16 were analyzed. Severity of CAD was determined by the presence and extent of coronary artery stenosis. Correlations between periodontal parameters, levels of inflammatory mediators, and CAD status were analyzed. Results: The extent of BOP exhibited a significant positive correlation with IL-18 in the Spearman Rank Correlation analysis (P = 0.039) indicating a correlation between periodontal inflammation and systemic IL-18 levels. When multiple regression analysis was performed, extent of CAL >/=3 mm (P = 0.045) and CAL >/=5 mm (P = 0.024) exhibited an association with IL-18, while CXCL16 was associated with CAL >/=5 mm (P = 0.040) and PD >/=7 mm (P = 0.047). Conclusions: A significant correlation was identified between periodontitis and systemic levels of IL-18 and CXCL16 in patients undergoing diagnostic coronary angiography.

27: Rheumatology (Oxford, England), 2010 May 14, 24(4)
Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis.

[Abstract]Objectives. To compare the pro-inflammatory cytokine profiles and the cytokine kinetics in patients with secondary macrophage activation syndrome (MAS) due to systemic-onset juvenile idiopathic arthritis (s-JIA) and in both active and inactive disease states of s-JIA (but no MAS), with those demonstrated in EBV-induced haemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD), and to investigate the significance of IL-18 in the pathogenesis of s-JIA. Methods. Five patients with MAS complicating s-JIA (MAS/s-JIA), 10 with HLH due to EBV infection (EBV-HLH), 22 with KD and 28 healthy controls were analysed. Cytokine concentrations (IL-18, IL-6, neopterin and TNF-alpha receptor Types I and II) were quantified in serum by ELISA. Results were compared with clinical features of MAS/s-JIA, including ferritin concentrations. Results. Serum IL-18 concentrations in MAS/s-JIA patients were significantly higher than those in EBV-HLH or KD patients (P < 0.05). Serum IL-6 concentrations in KD patients were significantly higher than those in EBV-HLH or MAS/s-JIA patients. Serum neopterin concentrations in EBV-HLH patients were significantly higher than those in MAS/s-JIA or KD patients. Serum IL-18 correlated positively with the following measurements of disease activity: CRP, ferritin, lactate dehydrogenase and other cytokines (P < 0.05). Serum concentrations of IL-18 in s-JIA patients remained elevated in the inactive phase of disease, whereas clinical parameters and other cytokines normalized. Conclusions. IL-18 may be an important mediator in s-JIA. Although serum Il-18 concentrations correlated with markers of the disease activity, IL-18 concentrations remained elevated even when other markers of disease activity normalized. Serum IL-18 concentration may be a promising indicator of the disease activity. The cytokine release pattern in MAS/HLH is different among patients with different aetiologies. Monitoring the cytokine profile, including IL-18, may be useful for differentiation of MAS/HLH and evaluation of disease activity in s-JIA.

28: Journal of immunotherapy (Hagerstown, Md. : 1997), 2010 Apr, 33(3)
Effect of IL-18 on expansion of gammadelta T cells stimulated by zoledronate and IL-2.

[Abstract]Zoledronate (Zol) has recently been shown to expand gammadelta T cells that play important roles in host defenses against infection and tumors. In this study, we examined effects of interleukin-18 (IL-18) on expansion of gammadelta T cells in human peripheral blood mononuclear cells (PBMCs) stimulated by Zol and IL-2. The expansion of gammadelta T cells stimulated by Zol and IL-2 was strongly promoted by exogenous IL-18, and to the contrary, inhibited by neutralizing anti-IL-18 receptor antibody. The gammadelta T cells that expanded in the presence of Zol, IL-2, and IL-18 exhibited the phenotype of effector memory cells characterized by CD44 (+), CD27 (-), and CD45RA (-). In addition, they expressed NKG2D, perforin, CD94, CD25, and CD122, and 15% to 40% of them were positive for CD56. Incubation of gammadelta T cells in the presence with IL-18 produced GM-CSF, IFN-gamma, and TNF-alpha at much higher levels than those incubated without IL-18. They showed strong cytotoxicity against tumor cells including mesothelioma cells and inhibited growth of xenograft of mesothelioma in mice. These observations indicate that IL-18 can efficiently promote expansion of gammadelta T cells with potent antitumor activity.

29: Molecular biology reports, 2010 Apr 28, 184(9)
Association of polymorphisms in the human IL-10 and IL-18 genes with rheumatoid arthritis.

[Abstract]The decrease of anti-inflammatory cytokine and increase of pro-inflammatory cytokine was observed in rheumatoid arthritis (RA). Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, has been demonstrated to suppress joint swelling and deformation in RA animal model. Interleukin-18 (IL-18), a widely distributed pro-inflammatory cytokine, induces the production of IFN-gamma, activate NK cells, and promote inflammation. Recent studies demonstrated that the serum IL-10 and IL-18 levels may be influenced by genetics and related to susceptibility to several autoimmune diseases. In the present study, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing techniques, we analyzed the genotype and allele distributions of two single nucleotide polymorphisms (SNP) loci in the promoter region of IL-10 and IL-18 genes (IL-10-592 A/C and IL-18-607 A/C loci, respectively). Our results indicated that IL-10-592 allelic and genotypic frequencies were significantly different between the RA patients and normal subjects (P < 0.05). In addition, significant differences of IL-10-592 allelic and genotypic frequencies were also detected between the patients with or without anti-cyclic citrullinated peptide antibody (anti-CCP) (P < 0.05). In contrast, allelic and genotypic frequencies of IL-18-607 did not show significant difference between RA patients and normal subjects (P > 0.05) or between anti-CCP-positive and anti-CCP-negative RA patients (P > 0.05). Furthermore, ELISA detection of IL-10 and IL-18 serum levels revealed that the genotype of IL-10-592 was associated with IL-10 serum level (P < 0.05), but the genotype and allele frequency of IL-18-607 was not associated with IL-18 serum level (P > 0.05). Taken together, our findings provide new insight for the polymorphism of IL-10 gene in the pathogenesis of RA.

30: Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 2010 Apr, 30(4)
[Expressions of interleukin 18 and prostaglandin E2 and their correlation in the synoviocytes of patients with osteoarthritis.]

[Abstract]OBJECTIVE: To explore the expression of interleukin 18 (IL-18) and prostaglandin E2 (PGE2) and their relationship in the synoviocytes of patients with osteoarthritis (OA). METHODS: The synovial tissues were obtained from 30 OA patients to isolate the synoviocytes for primary culture. The concentrations of IL-18 and PGE2 in the supernatants of synoviocyte culture were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The concentration of IL-18 averaged 51.559-/+27.614 pg/ml and PGE2 327.036-/+333.561 pg/ml in the supernatant of the synoviocytes. A significant positive correlation was noted between their expressions (r=0.863, P<0.01). CONCLUSION: IL-18 may induce the production of PGE2, and their interactions they may play an important role in the pathogenesis of OA.

31: Allergology international : official journal of the Japanese Society of Allergology, 2010 Apr 24, 59(2)
Importance of IL-18-Induced Super Th1 Cells for the Development of Allergic Inflammation.

[Abstract]Th1 cells, which express IL-18R, produce IFN-gamma in response to Ag and IL-2 and increase further production of IFN-gamma upon additional IL-18 stimulation. They simultaneously produce Th2 cytokines (IL-9 and IL-13), GM-CSF and chemokines (RANTES, MIP-1alpha). Human Th1 cells also produce IFN-gamma and IL-13 in response to anti-CD3 and IL-18. Recently, we demonstrated Th1 cells induce intrinsic type atopic asthma and dermatitis by production of Th1- and Th2-cytokines and chemokines. Here, we review the pathological roles of Th1 cells, stimulated with Ag and IL-18 in vivo, in the pathogenesis of allergic disorders by production of Th1 and Th2 cytokines and chemokines. Based on this unique function of Ag- plus IL-18-stimulated Th1 cells, we proposed to designate them as "super Th1 cells".

32: Toxicology in vitro : an international journal published in association with BIBRA, 2010 Apr 7, 8(1)
JNK pathway is required for TNCB induced IL-18 expression in murine keratinocytes.

[Abstract]The epidermal tissue of the skin is the first line of defense against exposure to microbial, chemical, and physical agents that cause cutaneous immune responses. Epidermal epithelial cells (keratinocytes) produce pro-inflammatory cytokine Interleukin-18 (IL-18) potentially relevant for the skin immune responses. Expression of IL-18 was investigated after exposure of murine keratinocytes PAM212 to pro-inflammatory stimuli, allergen TNCB (Trinitrichlorobenzen), LPS (lipopolysaccharide) or PMA (phorbol myristate acetate). IL-18 mRNA transcription and IL-18 secretion were detected by Real time-PCR and ELISA, respectively. The results showed that TNCB induced IL-18 expression in cultured murine keratinocytes in a dose-dependent manner, and it significantly stimulated IL-18 mRNA and protein expression at 10 muM. In addition, both LPS and PMA could increase the expression of IL-18 in murine keratinocytes. To determine the molecular mechanism involved, keratinocytes were pretreated with JNK, p38 or ERK MAPK inhibitors SP600125, SB203580, PD98059. We found that JNK inhibitors could significantly suppress IL-18 expression enhanced by TNCB. Western blot results showed that TNCB could induce the phosphorylation of JNK, but not p38 or ERK1/2. These results suggest that TNCB has an up-regulation effect on IL-18 production in murine keratinocyte cell line PAM212, and that the activation of the JNK signal pathway is the mechanism responsible for TNCB-induced IL-18 gene expression in murine keratinocytes.

33: Reproductive biology and endocrinology : RB&E, 2010 Apr 9, 8(1)
Endometrial caspase 1 and interleukin-18 expression during the estrous cycle and peri-implantation period of porcine pregnancy and response to early exogenous estrogen administration.

[Abstract]ABSTRACT: BACKGROUND: The role for endometrial secretion of cytokines during the establishment of pregnancy in a number of mammals is well established. The current study determined endometrial expression of caspase 1 (CASP1) and interleukin-18 (IL18) during the estrous cycle and early pregnancy, and following early estrogen administration, which induces conceptus loss during early development in pigs. Methods: Gilts were hysterectomized on either D 0, 5, 10, 12, 15 and 18 of the estrous cycle, or D 10, 12, 15 or 18 of pregnancy. The abundance of endometrial CASP1 mRNA was unaffected by day of the estrous cycle, however there was a 6 and 10-fold increase in expression on D 15 and 18 of pregnancy. Endometrial expression of IL18 mRNA increased 5-fold between D 10 to 18 in cyclic and pregnant gilts. Total recoverable IL18 in uterine flushings was greater in pregnant compared to cyclic gilts on D 15 and 18. In the second experiment, mated gilts were treated with either corn oil (CO) or estrogen (E) on D 9 and 10 and hysterectomized on either D 10, 12, 13, 15 or 17 of pregnancy. The current study localizes the presence of CASP1 to the epithelial layer of the endometrium for the first time. Further, a day x treatment interaction was detected for endometrial CASP1 mRNA and protein abundance as E stimulated an earlier increase on D 13 compared to CO gilts. Although IL18 mRNA expression remained unaltered from the E treatment, protein abundance was significantly attenuated on D 15 and 18 in response to E treatment. CONCLUSIONS: Endometrial expression of CASP1 and IL18 is associated with establishment of pregnancy in pigs. Alteration of CASP1 and IL18 following premature exposure of the uterus to estrogen during early pregnancy may contribute to conceptus loss between Days 15 to 18 of pregnancy.

34: Multiple sclerosis (Houndmills, Basingstoke, England), 2010 Mar 30, 44(2)
Interleukin 18 Receptor 1 expression distinguishes patients with multiple sclerosis.

[Abstract]Definition of dysregulated immune components in multiple sclerosis may help in the identification of new therapeutic targets. Deviation of the interleukin 18 receptor 1 (IL18R1) is of particular interest since the receptor is critical for experimental neuroinflammation. The objective of this study was to determine whether expression of IL18R1 varies between multiple sclerosis patients and controls, and to test genetic association of IL18R1 with multiple sclerosis. We used quantitative real-time PCR to assess mRNA levels of IL18R1 in cerebrospinal fluid and peripheral blood mononuclear cells of 191 patients with multiple sclerosis, 61 patients with clinically isolated syndrome and 168 controls having other neurological disorders. Association was tested in 2153 patients with multiple sclerosis and 1733 controls using 13 tagging single nucleotide polymorphisms within the IL18R1 gene. We found that patients with multiple sclerosis had increased IL18R1 mRNA expression in both cerebrospinal fluid cells (p < 0.05) and peripheral blood mononuclear cells (p < 0.05) compared with controls. Patients with clinically isolated syndrome had elevated levels compared with controls in cerebrospinal fluid cells (p < 0.001) but not in peripheral blood mononuclear cells. The gene was not associated to multiple sclerosis. We conclude that the increased expression of IL18R1 may contribute pathogenically to disease and is therefore a potential therapeutic target. The absence of a genetic association in the IL18R1 gene itself suggests regulation from other parts of the genome, or as part of the inflammatory cascade in multiple sclerosis without a prime genetic cause.

35: Annals of medicine, 2010 Mar 30, 44(2)
Interleukin-18 gene polymorphism and markers of subclinical atherosclerosis. The Cardiovascular Risk in Young Finns Study.

[Abstract]Abstract Background and aim. Interleukin-18 (IL-18) is a pro-atherosclerotic cytokine. We wanted to evaluate whether IL-18 gene polymorphism associates independently of risk factors, with early subclinical markers of atherosclerosis (intima-media thickness (IMT), coronary artery compliance (CAC), and flow-mediated dilatation (FMD)) in a population of young healthy Caucasian adults. Methods. This study was based on the on-going Cardiovascular Risk in Young Finns Study consisting of 2260 young adults, mean age being 31.7 (range 24-39 years) (1247 women and 1013 men). Results. Five studied tagSNPs formed six major haplotypes, which accounted for 99.9% of all variation of the IL-18 gene. According to adjusted analysis of variance, the IL-18 gene polymorphism did not associate with subclinical atherosclerosis in the whole study population. However, one major haplotype associated differently among men and women with IMT (P = 0.011). Male carriers of a major CCTgT haplotype (n = 441) seemed to have a lower IMT when compared to the non-carriers (-0.016 mm, 95% confidence interval (CI) -0.028 to -0.004, P = 0.014). Among women no significant associations were observed. Conclusions. Among all study subjects, the polymorphism of the IL-18 gene is not associated with subclinical markers of atherosclerosis. However, among men one major IL-18 haplotype seemed to associate with substantially lower IMT values.

36: Veterinary immunology and immunopathology, 2010 Aug 15, 136(3-4)
Expression, purification and monoclonal antibodies preparation of recombinant equine mature interleukin-18.

[Abstract]IL-18 is a cytokine originally discovered as an important modulator of immune responses and subsequently shown to be pleiotropic. In this report, we expressed the recombinant equine mature interleukin-18 (rEMIL-18) in E. coli and purified it by nickel affinity gel column chromatography. Purified rEMIL-18 had biological activity commensurate with recombinant human IL-18, as determined by its synergistic effect with recombinant human IL-12 (rhIL-12) on the induction of IFN-gamma gene expression in equine peripheral blood mononuclear cells (PBMC). Following intraperitoneal (i.p.) immunization of BALB/c mice with rEMIL-18, nine monoclonal antibodies (mAbs) against equine interleukin-18 (EIL-18) were obtained and characterized. These mAbs recognized different epitopes on equine mature interleukin-18 (EMIL-18) protein based on their reactivity with two peptides containing different amino acid sequences and one of these mAbs has neutralization activity against EIL-18 in an IFN-gamma-induction assay.

37: Immunity, 2010 Mar 26, 32(3)
Interleukin-18 in Intestinal Inflammation: Friend and Foe?

[Abstract]Genetic studies and other experimental data have linked inflammatory bowel diseases with inflammasome activation. In this issue of Immunity, Zaki et al. (2010) and Dupaul-Chicoine et al. (2010) provide a detailed characterization of the regulatory task of the inflammasome in intestinal epithelial cells.

38: Cardiovascular diabetology, 2010 Mar 23, 9(1)
The role of interleukin-18 in the metabolic syndrome.

[Abstract]ABSTRACT: The metabolic syndrome is thought to be associated with a chronic low-grade inflammation, and a growing body of evidence suggests that interleukin-18 (IL-18) might be closely related to the metabolic syndrome and its consequences. Circulating levels of IL-18 have been reported to be elevated in subjects with the metabolic syndrome, to be closely associated with the components of the syndrome, to predict cardiovascular events and mortality in populations with the metabolic syndrome and to precede the development of type 2 diabetes. IL-18 is found in the unstable atherosclerotic plaque, in adipose tissue and in muscle tissue, and is subject to several regulatory steps including cleavage by caspase-1, inactivation by IL-18 binding protein and the influence of other cytokines in modulating its interaction with the IL-18 receptor. The purpose of this review is to outline the role of IL-18 in the metabolic syndrome, with particular emphasis on cardiovascular risk and the potential effect of life style interventions.

39: Human immunology, 2010 Mar 18, 44(2)
Haplotype Analysis of the Interleukin 18 (IL-18) Gene in Czech Patients with Allergic Disorders.

[Abstract]The interleukin-18 (IL-18) gene on chromosome 11q22 has been suggested a susceptibility factor for allergies. To test a possible role of IL-18 polymorphisms in Czech population, case-control study including 958 subjects (633 allergic patients and 325 healthy controls) was performed. An allele-specific polymerase chain reaction was used to analyze variants at positions -607C/A (rs1946518) and -137G/C (rs187238) in the promoter region together with the PCR-RFLP method for the detection of polymorphism at position -140C/G (previously -133C/G, rs360721) in intron 1 of the IL-18 gene. The -1297C/T (rs360719) polymorphism was genotyped by RT-PCR, using a pre-development TaqMan allele discrimination assay. There were no significant differences in distribution of alleles or genotypes in any of four SNPs in the IL-18 gene between controls and patients. However, subsequent analysis revealed a significant difference in haplotype frequencies between the allergic patients and healthy subjects (p<0.01). Haplotype formed by -1297C/-607A/-137C/-140C alleles occurred significantly more frequently in patients than controls (0.0433 vs. 0.0129; p<0.0003; p(corr)< 0.01, OR=3.37; 95% CI:1.59-7.14). In contrast, there was no relationship among the IL-18 variants and total serum IgE level. Our results indicate that promoter polymorphisms in the IL-18 gene act in interaction and could play a role in allergic disorders.

40: Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals, 2010 Mar 17, 44(2)
Combination of urinary kidney injury molecule-1 and interleukin-18 as early biomarker for the diagnosis and progressive assessment of acute kidney injury following cardiopulmonary bypass surgery: a prospective nested case-control study.

[Abstract]The aim of this nested case-control study was to assess the combined use of urinary kidney injury molecule (KIM)-1 and interleukin (IL)-18 for acute kidney injury (AKI) after cardiopulmonary bypass surgery (CPB). From a cohort of 122 subjects who underwent CPB, serial urinary KIM-1 and IL-18 concentrations were determined in 30 AKI and 92 non-AKI patients. An increased level of urinary KIM-1 was associated with the occurrence of AKI, whereas an increased level of IL-18 was related to progressive AKI. The combination of these two biomarkers facilitates the early diagnosis and assessment of the likely progression of AKI after CPB.

41: Acta diabetologica, 2010 Feb 26, 18(3)
Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

[Abstract]Diabetic complication is comprised of a wide variety of pathophysiological factors involving proinflammatory cytokines, adipokines, and oxidative stress, among others. Each of these complications differs in their incidence and the stage of their occurrence. We examined cytokines and stress markers in 48 patients with type 2 diabetes mellitus and compared the difference of their contribution to pathogenesis between nephropathy and other diabetic complications. Hemoglobin A1c correlated with the level of low-density lipoprotein-cholesterol, and significantly elevated in the severe macroangiopathy group. Cystatin C increased in the severe microangiopathy groups but did not increase in the macroangiopathy group. The levels of interleukin 18 (IL-18), high-sensitive CRP (H-CRP), liver-type fatty acid binding protein, and 8-hydroxy-2-deoxyguanosine increased in the severe microangiopathy group. These data suggest the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy. In particular, IL-18 and H-CRP were significantly elevated only in the severe nephropathy group but did not significantly elevate in other complications. These data suggest another effect of IL-18 on glomerulus in addition to its proinflammatory effect. In conclusion, we propose that IL18 has a specific role that contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

42: Research in veterinary science, 2010 Feb 2, 28(5)
The protective effect of a Toxoplasma gondii SAG1 plasmid DNA vaccine in mice is enhanced with IL-18.

[Abstract]More effective vaccines against Toxoplasma gondii may contribute to the control of this pathogen that has major veterinary and public health significance. In this study, two recombinant plasmids pcDNA/TgSAG1 and pVAX/mIL-18 containing T. gondii SAG1 (TgSAG1) and murine cytokine interleukin-18 (IL-18) were evaluated for their ability to protect mice against T. gondii challenge. Mice were given two intramuscular immunizations 3weeks apart, and challenged with T. gondii 3weeks later. All animals vaccinated with pcDNA/TgSAG1 alone or with pVAX/mIL-18 developed specific anti-TLA (T. gondii lysate antigen) antibodies and specific lymphocyte proliferative responses. Co-injection of pVAX/mIL-18 significantly increased the production of IFN-gamma and IL-2. Further, challenge experiments showed that co-immunization with pVAX/mIL-18 significantly (P<0.05) increased the survival rate (60%), compared with pcDNA/TgSAG1 alone (40%). Therefore, codelivery of the IL-18-secreting plasmid potentiates the induction and maintenance of the type 1 helper T-cell immune response and may be a potent strategy for enhancing the protective efficacy of vaccines against T. gondii.

43: Journal of virology, 2010 Feb 3, 201(4)
Interleukin 18 co-expression during respiratory syncytial virus infection results in enhanced disease mediated by natural killer cells.

[Abstract]Respiratory Syncytial Virus (RSV) causes bronchiolitis, the main cause of infantile hospitalization. Immunity against re-infection is poor, and there is great interest in boosting vaccine responses using live vectors expressing host cytokines. We therefore constructed recombinant RSV expressing murine IL-18 (RSV/IL-18), a cytokine capable of inducing strong anti-viral immune responses. In vitro RSV/IL-18 replicated at wildtype levels and produced soluble IL-18. In na?ve BALB/c mice RSV/IL-18 infection significantly increased both IL-18 mRNA and protein and attenuated peak viral load 3-fold. Despite reduced viral load, RSV/IL-18 infection caused a biphasic weight loss at days 2 and 6 post infection, not seen in wildtype infection. Day 2 disease was associated with enhanced pulmonary natural killer cell number and activity, and was prevented by NK cell depletion during infection; day 6 disease correlated with CD8 T cell recruitment and was enhanced by NK cell depletion. IL-18 expression during priming also enhanced RSV specific antibody responses and T cell responses on secondary RSV infection. Therefore, while IL-18 boosts anti-viral immunity and reduces viral load, its co-expression worsened disease. This is the first recombinant RSV with this property, and these are the first studies to demonstrate that NK cells can induce pathology during pulmonary viral infections.

44: Journal of neuroinflammation, 2010 Jan 29, 7(1)
Interleukin 18 in the CNS.

[Abstract]ABSTRACT: Interleukin (IL)-18 is a cytokine originally discovered as an important modulator of immune responses and subsequently shown to be pleiotropic. IL-18 and its receptors are expressed in the central nervous system (CNS) where they participate in neuroinflammatory/neurodegenerative processes but also influence homeostasis and behavior. Work on IL-18 null mice, localization of the IL-18 receptor complex in neurons, and demonstration of neuronal expression of decoy isoforms of the receptor subunits are beginning to reveal the complexity and the significance of the IL-18 system in the CNS. This review summarizes current knowledge on the central role of IL-18 in health and disease.

45: Calcified tissue international, 2010 Jan 29, 184(3)
IL-18 Inhibits TNF-alpha-Induced Osteoclastogenesis Possibly via a T Cell-Independent Mechanism in Synergy with IL-12 In Vivo.

[Abstract]It has recently been reported that tumor necrosis factor (TNF)-alpha has the ability to accelerate osteoclastogenesis. We previously reported that the proinflammatory cytokine interleukin (IL)-18 inhibits TNF-alpha-mediated osteoclastogenesis in mouse bone marrow cultures. In the present study, the effect of IL-18 on TNF-alpha-mediated osteoclastogenesis was investigated in vivo. We administered TNF-alpha with or without IL-18 into the supracalvaria of mice. The number of osteoclasts in the suture of the calvaria was increased in mice administered TNF-alpha. The number of osteoclasts in mice administered both TNF-alpha and IL-18 was lower than that in mice administered TNF-alpha alone. We previously showed that IL-12 and IL-18 synergistically inhibit TNF-alpha-mediated osteoclastogenesis in vitro. To assess the ability of these two cytokines to synergistically inhibit TNF-alpha-induced osteoclastogenesis in vivo, mice were administered the two cytokines at doses that did not inhibit osteoclast formation. The combination of IL-12 and IL-18 markedly inhibited TNF-alpha-induced osteoclastogenesis in vivo. To evaluate how IL-12 and IL-18 synergistically affect TNF-alpha-induced osteoclastogenesis, the IL-18 receptor (IL-18R) and IL-12R expression levels were analyzed by RT-PCR in bone marrow cells cultured with IL-12 or IL-18. IL-18R mRNA was increased in cells cultured with IL-12, while IL-12R mRNA was increased in cells cultured with IL-18. In addition, IL-18 inhibited TNF-alpha-induced osteoclastogenesis in mice with T-cell depletion caused by anti-CD4 and anti-CD8 antibodies. The present results suggest that IL-18 may inhibit TNF-alpha-mediated osteoclastogenesis in vivo via a T cell-independent mechanism.

46: Brain research bulletin, 2010 Jan 21, 184(3)
Interleukin-18 promoter polymorphisms and risk of ischemic stroke.

[Abstract]Ischemic stroke (IS) is a major cause of morbidity and mortality around the world. Interleukin -18 (IL-18) plays an important role in the pathogenesis of IS and IL-18 promoter polymorphisms have been shown to be associated with levels of expression of IL-18. We investigated the association of two functional polymorphisms in IL-18 promoter, -607C/A (rs1946518) and -137G/C (rs187238), with the risk of ischemic stroke in a Han Chinese population of 423 patients and 384 healthy controls matched for sex and age. The results revealed that the -607C allele was associated with an increased risk of IS with an odds ratios (OR) of 1.358 (P=0.002, power=100%) and the presence of the -137G allele was correlated with increased the risk of IS in the subtype of patients with large artery atherosclerosis (LAA) (OR=1.583, P=0.02, power=94%). Patients with the -607C/-137G haplotype also had significantly increased risk of IS compared to controls (OR=1.341, P=0.005, power=100%). Our findings suggest that these functional polymorphisms in the IL-18 promoter are involved in development of IS in the Han Chinese population.

47: Cytokine, 2010 Jan 20, 184(3)
Does interleukin-18 or tumour necrosis factor-alpha have an independent association with the risk of coronary heart disease? Results from a prospective study in New Zealand.

[Abstract]Background: The pro-inflammatory cytokines, interleukin (IL)-18 and tumour necrosis factor-alpha (TNFalpha) may play a role in coronary heart disease (CHD). We aimed to extend data on their relationships to the risk of CHD in generally healthy populations. Methods: During 5.5years follow-up in the Fletcher Challenge general population cohort there were 256 CHD cases, and 615 controls were matched for age and sex. Baseline plasma levels of IL-18 and TNFalpha were related to CHD risk in available samples (77%). Results: Plasma levels of IL-18 (11% increase in mean, p=0.01) and TNFalpha (10% increase in mean p=0.024) were significantly elevated in CHD cases versus controls. In univariable models IL-18 was associated with CHD risk (odds ratio [OR] upper third to lower third, 1.63; 95% CI 1.08, 2.46), but TNFalpha was not (OR 1.33; 95% CI 0.87, 2.02).After adjusting for major CHD risk factors and CRP, the association of IL-18 with CHD risk was attenuated (OR 1.69; 95% CI 0.94, 3.03). Conclusions: IL-18, but not TNFalpha, had a non-negligible association with CHD risk, although the association of IL-18 with risk was weak after full adjustment. These cytokines may play a role in CHD pathology, but may not be robust risk biomarkers.

48: Clinical and experimental immunology, 2010 Jan 19, 184(3)
Inhibition of transforming growth factor-beta signalling attenuates interleukin (IL)-18 plus IL-2-induced interstitial lung disease in mice.

[Abstract]Summary Interstitial lung disease (ILD) is an intractable disease induced by various factors in humans. However, there is no universally effective treatment for ILD. In this study, we investigated the role of transforming growth factor (TGF)-beta signalling in the pathogenesis of ILD by using model mice. Injection of interleukin (IL)-18 plus IL-2 in C57BL6 (B6) mice resulted in acute ILD by infiltration of natural killer (NK) cells and a significant increase of TGF-beta mRNA in the lung. To examine the pathogenetic role of TGF-beta in ILD mice, we used SB-431542 (4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]-benzamide), which is a potent and selective inhibitor of TGF-beta receptor I (TbetaRI), also known as activin receptor-like kinase 5 (ALK5). Treatment of B6-ILD mice with SB-431542 resulted in improvement of ILD, delay in mortality, reduction of the expression of interferon (IFN)-gamma and IL-6 in the lungs. The same treatment also decreased significantly the percentage of natural killer (NK) cells in the lungs (P < 0.05) and mRNA expression levels of certain chemokines such as CCL2, CCL3, CCL4, CCL5 and CXCL10 in B6-ILD. These findings were confirmed by IL-18 plus IL-2 treatment of Smad3-deficient (Smad3(-/-)) mice (P < 0.05). Our results showed that inhibition of TGF-beta signalling reduced the percentage of NK cells and the expression of certain chemokines in the lungs, resulting in improvement of ILD. The findings suggest that TGF-beta signalling may play an important role in the pathogenesis of IL-18 plus IL-2-induced ILD in mice.

49: Journal of clinical immunology, 2010 Jan 19, 184(3)
Selective Deletion of CD8(+) Cells Upregulated by Caspases-1 via IL-18 in Mice Immunized with Major Outer Membrane Protein of Shigella dysenteriae 1 Following Infection.

[Abstract]INTRODUCTION: Mucosal lymphoid changes were observed in cryopreserved rectal tissues obtained from BALB/c mice infected with Shigella dysenteriae 1, immunized with 57-kDa major antigenic outer membrane protein, and infection after immunization. DISCUSSION: Our data suggested that caspase-3 is downregulated in CD4(+) cells of immunized BALB/c mice following infection with substantial increased expression of interleukin (IL)-2 and interferon (IFN)-gamma, while caspase-1 is upregulated in CD8(+) cells with decreased expression of IL-4 and IL-10. This indicated an involvement of Fas-mediated lytic pathway for selective deletion of CD8(+) cells out of CD3(+) T cells. IL-18 promotes inflammation and induces IFN-gamma and tumor necrosis factor (TNF)-alpha as the expression of IFN-gamma and TNF-alpha cytokines was evident in this study. It is assumed that the role of caspase-1 in inducing the CD4+ T cell activity increased with IL-18 rather than CD8+ suppressor cell activity. Bcl-2 is capable of inhibiting the Fas/Fas-L-mediated cell death for helper cells. Overall, the findings indicate that majority of the apoptotic cells were CD8(+) T cells in the groups of infection following immunization, and there might be a selective deletion of T lymphocytes mediated by caspase-1 via IL-18.

50: The Journal of infectious diseases, 2010 Jan 15,
HIV-1 Causes an Imbalance in the Production of Interleukin-18 and Its Natural Antagonist in HIV-Infected Individuals: Implications for Enhanced Viral Replication.

[Abstract]Background. Concentrations of interleukin (IL)-18 increase in the circulation of human immunodeficiency virus (HIV)-infected persons. However, nothing is known concerning the regulation of IL-18-binding protein (IL-18BP), which neutralizes IL-18 in vivo. This issue is addressed in the present study. Methods. Serum samples obtained from healthy subjects and HIV-infected patients were analyzed by enzyme-linked immunosorbent assay to determine their IL-18 and IL-18BP contents. Human monocyte-derived macrophages (MDMs) were infected in vitro with HIV type 1 (HIV-1), and the production of these 2 cytokines by these cells was measured. Finally, we determined the effect of IL-18 on HIV-1 replication in human cells. Results. In contrast to IL-18 levels, IL-18BP levels decreased in the serum of HIV-infected patients. This decrease resulted in enhanced levels of free IL-18 in the serum of such patients. The infection increased production of IL-18 but decreased that of IL-18BP in MDMs. IL-10 and transforming growth factor-beta, concentrations of which are increased in HIV-infected persons, also decreased production of IL-18BP by human MDMs. Finally, recombinant human IL-18 enhanced HIV-1 replication in human CD4(+) T cells. Conclusions. Production of IL-18 and its antagonist becomes imbalanced in HIV-1-infected persons. The infection and the cytokine milieu play a role in this decreased production. The increased biological activities of IL-18 may enhance viral replication in human CD4(+) T cells.

51: American journal of hypertension, 2010 Jan 14,
Association of Interleukin-18 Levels With Global Arterial Function and Early Structural Changes in Men Without Cardiovascular Disease.

[Abstract]BackgroundIncreased levels of interleukin-18 (IL-18) have been related to plaque progression and vulnerability and cardiovascular outcomes. Arterial functional and structural characteristics and endothelial/inflammatory activation are important determinants of cardiovascular performance and predictors of risk. We investigated whether IL-18 is a determinant of global arterial function and early structural changes in men.MethodsWe evaluated arterial structural and functional characteristics (carotid-femoral pulse wave velocity (PWV), central aortic pressures, wave reflection indexes, flow-mediated dilation of the brachial artery, and common carotid intima-media thickness (IMT)) and we measured systemic inflammatory markers in 97 men (mean age 57.8 +/- 8.6 years) without manifest cardiovascular/atherosclerotic disease.ResultsMultivariable analysis adjusting for age, mean pressure, other risk factors, high-sensitivity C-reactive protein (hsCRP), and treatment showed independent associations between IL-18 level and carotid-femoral PWV (P < 0.01) and IMT (P = 0.03). On the other hand, no relationship between IL-18 and flow-mediated dilation, central pressures or augmentation index (AIx) was found. The combination of higher IL-18 level with higher carotid-femoral PWV and carotid IMT values showed greater effect on 10-year risk of a cardiovascular event.ConclusionsIL-18 level is independently associated with aortic stiffening and carotid early atherosclerosis. This finding underlines the important role of IL-18 as a marker of arterial damage, and implies a contribution of this compound to the pathophysiology of cardiovascular disease.American Journal of Hypertension 2010; doi:10.1038/ajh.2009.256.

52: Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2010 Jan, 26(1)
[N-acetylcysteine antagonizes the Interleukin-18-induced expression of TNF-alpha and IL-6 in mouse vascular smooth muscle cells.]

[Abstract]AIM: To explore the effect of N-acetylcysteine(NAC)on the interleukin(IL)18-induced expression of tumor necrosis factor (TNF) alpha and interleukin(IL) 6 in mouse vascular smooth muscle cells(VSMC). METHODS: VSMC was stimulated with various concentrations of IL-18 for different times after addition of NAC(5 mmol/L) for 1 h. The messenger ribonucleic acid(mRNA) expression of TNF-alpha and IL-6 was measured by RT-PCR and the protein secretion of the two cytokines was determined by ELISA method. Western blot was used to analyze the activation of NF-kappaB in VSMC. RESULTS: IL-18 significantly increased the mRNA expression and protein secretion of TNF-alpha and IL-6 (P>0.01) in a dose-dependent and a time-dependent ways. NAC inhibited the mRNA expression and protein secretion of TNF-alpha and IL-6 induced by IL-18(P>0.01). Western blot results showed the NAC inhibited the IL-18-induced activation of NF-kappaB in VSMC. CONCLUSION: N-acetylcysteine antagonizes the production of TNF-alpha and IL-6 induced by IL-18 in VSMC.

53: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2009 Dec 22, 286(2)
Differentiation of Human SH-SY5Y Neuroblastoma Cells by All-Trans Retinoic Acid Activates the Interleukin-18 System.

[Abstract]The clinical prognosis of children with high-stage neuroblastoma is still poor. Therapeutic approaches include surgery and cellular differentiation by retinoic acid, but also experimental interleukin-based immune modulation. However, the molecular mechanisms of all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells are incompletely understood. Herein, we examined the effect of ATRA on the activity of the interleukin-18 (IL-18) system in human SH-SY5Y neuroblastoma cells. It is shown that SH-SY5Y cells express IL-18 receptor (IL-18R) and the secreted antagonist IL-18-binding protein (IL-18BP), but no IL-18. SH-SY5Y cells are highly sensitive to ATRA treatment and react by cellular differentiation from a neuroblastic toward a more neuronal phenotype. This was associated with induction of IL-18 and reduction of IL-18BP expression, while IL-18R expression remained stable. Thereby, we identified the IL-18 system as a novel target of ATRA in neuroblastoma cells that might contribute to the therapeutic properties of retinoids in treatment of neuroblastoma.

54: Scandinavian journal of urology and nephrology, 2009 Dec 18, 286(2)
Association of interleukin-18 gene polymorphisms with calcium oxalate kidney stone disease.

[Abstract]Abstract Objective. The interleukin-18 (IL-18) encoding gene has three common single-nucleotide polymorphisms at -607C/A, -137G/C and +105A/C, which have been reported to be associated with several diseases. The aim of this study is to test whether IL-18 polymorphisms could act as genetic markers for renal stone disease. Material and methods. A control group of 104 healthy subjects, and 272 patients with recurrent calcium oxalate stones were examined. Polymerase chain reaction-based restriction endonuclease analysis was used to detect IL-18 polymorphisms. Results. The patient and control groups differed significantly in genotypic expression of the IL-18 +105A/C polymorphism. The prevalence of the A/C + C/C genotypes in the patients was higher than that in the controls. The allelic frequency of IL-18 +105A/C differed significantly between the patients and the controls. The odds ratio (OR) of the A/C heterozygote of IL-18 +105A/C associated with urolithiasis was 2.772. The OR of the A/C + C/C genotypes of IL-18 +105A/C associated with urolithiasis was 3.097. The OR per copy of the C allele of IL-18 +105A/C associated with urolithiasis was 4.143. There were also significant differences in the prevalence of genotype IL-18 -137G/C polymorphisms between the patients and controls. The distribution of the G/G homozygote in the patients was higher than that in the controls. There was no significant difference in genotype and allelic frequency at the IL-18 -607C/A polymorphism between patients and control subjects. Conclusion. The results indicate that IL-18 +105A/C polymorphisms may play a role in the development of urolithiasis.

55: Fertility and sterility, 2009 Dec 8, 7(1)
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor inducible-14 might regulate the effects of interleukin 18 and 15 in the human endometrium.

[Abstract]Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) could play a role in the regulation of interleukin (IL)-15 and IL-18, cytokines crucial for angiogenesis and uterine natural killer (uNK) cell recruitment during embryo implantation. We therefore confirmed the endometrial presence of TWEAK/fibroblast growth factor inducible-14 (Fn-14) and documented simultaneously the cytotoxic KIR receptor (NKp46) of uNK cells in the human endometrium while TWEAK, Fn-14, IL-15, and IL-18 mRNA were quantified by real-time polymerase chain reaction in relation to the recruitment of CD(56+) cells among fertile control women and patients who had failed to implant after assisted reproduction treatment.

56: Journal of translational medicine, 2009 Dec 10, 7(1)
Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18.

[Abstract]ABSTRACT: BACKGROUND: Liposomal doxorubicin (Doxil) is a cytotoxic chemotherapy drug with a favorable hematologic toxicity profile. Its active drug, doxorubicin, has interesting immunomodulatory properties. Here, the effects of Doxil on surviving tumor cell immunophenotype were investigated. METHODS: Using ID8 murine ovarian cancer cells, the immunomodulatory effects of Doxil were studied by measuring its impact on ovarian cancer cell expression of MHC class-I and Fas, and susceptibility to immune attack in vitro. To evaluate the ability of Doxil to cooperate with cancer immunotherapy, the interaction between Doxil and Interleukin 18 (IL-18), a pleiotropic immunostimulatory cytokine, was investigated in vivo in mice bearing ID8-Vegf tumors. RESULTS: While Doxil killed ID8 tumor cells in a dose-dependent manner, tumor cells escaping Doxil-induced apoptosis upregulated surface expression of MHC-I and Fas, and were sensitized to CTL killing and Fas-mediated death in vitro. We therefore tested the hypothesis that the combination of immunotherapy with Doxil provides positive interactions. Combination IL-18 and Doxil significantly suppressed tumor growth compared with either monotherapy in vivo and uniquely resulted in complete tumor regression and long term antitumor protection in a significant proportion of mice. CONCLUSION: These data demonstrate that Doxil favorably changes the immunophenotype of a large fraction of the tumor that escapes direct killing thus creating an opportunity to expand tumor killing by immunotherapy, which can be capitalized through addition of IL-18 in vivo.

57: European journal of clinical investigation, 2009 Nov 24, 389(4)
Interleukin-18 levels are associated with low-density lipoproteins size.

[Abstract]Eur J Clin Invest 2009Abstract Introduction Both low-density lipoproteins (LDL) size and serum interleukin (IL)-18 levels have been shown to be predictors of cardiovascular morbidity and mortality. However, it is still unknown whether IL-18 levels are independently associated with LDL size. Methods In this cross-sectional study including 53 premenopausal women (18-45 years), LDL size (by gradient gel electrophoresis), serum IL-18, high-sensitivity C-reactive protein (hs-CRP), serum lipids, insulin sensitivity (S(I), by frequently sampled intravenous glucose tolerance test) were measured. Results LDL size correlated with IL-18 (r = -0.38, P = 0.006), hs-CRP (r = -0.40, P = 0.003), S(I) (r = 0.36, P = 0.011), serum triglycerides (r = -0.32, P = 0.018) and high-density lipoproteins (HDL)-cholesterol (r = 0.40, P = 0.003). When these variables were entered into a regression model, serum IL-18 (beta = -0.26, P = 0.04), triglycerides (beta = -0.29, P = 0.02) and HDL-cholesterol (beta = 0.34, P = 0.01) levels were independently associated with LDL size, accounting for 42% of the variance (P < 0.001). Serum hs-CRP levels and S(I) were not significant independent predictors of LDL size in this model. Conclusions This is the first report showing that elevated IL-18 levels are associated with reduced LDL size, independent of other inflammatory and metabolic risk factors. Future prospective studies are needed to evaluate the predictive role of IL-18 as an inflammatory marker of LDL size and the development of subclinical and/or clinical atherosclerosis.

58: Human immunology, 2009 Dec 1, 30(23)
Impact of interleukin-18 polymorphisms -607 and -137 on clinical characteristics of renal cell carcinoma patients.

[Abstract]Current evidence suggests that chronic inflammation is associated with tumor development and progression. Interleukin-18 (IL-18) plays a central role in inflammation and the immune response, contributing to the pathogenesis and pathophysiology of infectious and inflammatory diseases. The objective of this study was to determine whether the presence of IL-18 polymorphisms -137 G/C (rs187238) and -607 A/C (rs1946518) was associated with size, grade, T, N, M stage and survival in patients with renal cell carcinoma (RCC). The study cohort included 158 patients with RCC. Control group consisted of 506 samples from Spanish population. The studied IL-18 gene polymorphisms did not influence susceptibility to RCC in the analyzed group of patients (IL-18-607, p=0.318; IL18-137 p=0.740) but may contribute to disease onset and aggressiveness. IL-18-607 CC genotype was significantly associated with higher tumor size (p=0.001), grade (p=0.030), T (p=0.001), M (p=0.012) and stage (p=0.002). IL-18-103 GG genotype was correlated with higher tumor size (p=0.036), grade (p=0.017), T (p=0.026) and stage (p=0.011). The Cox proportional hazard model showed that nuclear grade and stage grouping were independent prognostic factors but IL-18 polymorphism was not. Polymorphism variants in the IL-18 gene (IL-18-607 and -137) may be associated with a worse prognosis for RCC. High levels of IL-18 production may play a major role in the growth, invasion and metastasis of renal cancer.

59: Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2009 Dec, 25(12)
[Expression and analysis of recombinant chicken IL-18 in Pichia pastoris.]

[Abstract]AIM: Expression and analysis of recombinant chicken IL-18 in Pichia pastoris. METHODS: Chicken IL-18 mature peptide gene was amplified from the recombinant plasmid pMD18-T-ChIL-18 by PCR, and was subcloned into Pichia pastoris expression vector pPICZalphaA to construct the recombinant plasmid pPICZalphaA-ChIL-18. After identified by restriction enzymes digestion analysis, PCR and DNA sequencing, the recombinant plasmid was transformed into Pichia pastoris X-33.Then choosing the multi-copy recombinant strains to be induced for expression.Then the bioactivity of rchIL-18 was analysed by Western blot, ELISA and MTT after purified by Sephadex G-100 column. RESULTS: The chicken IL-18 with the immunogenicity was secreted by Pichia pastoris. It could induce T lymphocytes proliferation and secreting IFN-gamma in vitro. CONCLUSION: The chicken IL-18 with obvious biological activity is secreted by Pichia pastoris X-33.

60: Scandinavian cardiovascular journal : SCJ, 2009 Dec 4, 132(2-4)
Plasma IL-18 and IL-18BP are altered differently in reverse remodeling following aortic valve replacement.

[Abstract]Abstract Objectives. Patients with aortic stenosis (AS) develop left ventricular remodeling characterized by changes in extracellular matrix (ECM) and cardiomyocyte-hypertrophy. Aortic valve replacement (AVR) reverses this process (reverse remodeling). We examined plasma levels of interleukin-18 (IL-18) and its binding protein (IL-18BP) before and after AVR for AS since these mediators have been shown experimentally to exert effects on myocardial remodeling. Design. Plasma levels of IL-18 and IL-18BP were analyzed in 22 patients with AS undergoing AVR, preoperatively, two days, six and 12 months postoperatively. Echocardiography and functional testing were performed. Results. IL-18BP was significantly increased by 28% and 15% at two days and six months after AVR, compared to preoperative values. In contrast, IL-18 showed a later peak (increased by 24% at 12 months postoperatively) when IL-18BP was normalized. IL-18 correlated positively with deceleration time (R = 0.44) at this time-point which might indicate an association with diastolic function. Conclusions. We report for the first time that plasma IL-18 and IL-18BP are differentially regulated after AVR for AS with an early increase in IL-18BP postoperatively followed by a later peak in IL-18 at 12 months. Given the known effects of these mediators on myocardial remodeling and function, they might play a role in the reverse and remodeling process associated with AVR.

61: Current HIV research, 2009 Dec 3, 132(2-4)
Potential Role of IL-18 in the Immunopathogenesis of AIDS, HIV-Associated Lipodystrophy and Related Clinical Conditions.

[Abstract]IL-18 is a pleiotropic and multifunctional proinflammatory cytokine that is often produced in response to a viral infection. The biological activities of the cytokine are tightly controlled by its natural antagonist, IL-18 binding protein (IL-18BP), as well as by activation of caspase-1, which cleaves the precursor form of IL-18 into its biologically mature form. The cytokine plays an important role in both innate and adaptive antiviral immune responses. Depending upon the context, it can promote TH1, TH2 and TH17 responses. Increased serum concentrations of IL-18 and concomitantly decreased concentrations of its natural antagonist have been described in HIV-infected persons as compared to HIV-seronegative healthy subjects. We discuss in this review article how increased biological activities of IL-18 contribute towards immunopathogenesis of AIDS, HIV-associated lipodystrophy syndrome and related metabolic disturbances. While the advent of potent anti-HIV drugs has significantly enhanced life span of HIV-infected patients, it has also increased the number of these patients suffering from metabolic disorders. The cytokine may prove to be a useful target for therapeutic intervention in these patients.

62: European journal of immunology, 2009 Nov 30, 103(12)
A role of interleukin 18 for protective immunity against Mycobacterium tuberculosis.

[Abstract]Tuberculosis remains the most hazardous bacterial infection worldwide. The causative agent, Mycobacterium tuberculosis, is a facultative intracellular pathogen of resting macrophages. Interferon gamma secreted by natural killer, CD4 T helper (Th) 1 and CD8 T cells upon instruction by interleukin (IL)-12 and 18 activates macrophages to restrict mycobacterial growth. Production of both cytokines is induced by Toll-like-receptor (TLR) signalling in dendritic cells and macrophages. Mice deficient for the TLR adaptor, MyD88, are highly susceptible to M. tuberculosis infection. Shared usage of MyD88 by signalling cascades for TLRs and receptors for IL-1 and IL-18 prompted us to revisit the role of IL-18 during experimental infection with M. tuberculosis. We show that mice deficient for IL-18 and MyD88 but not for IL-18R promptly succumbed to M. tuberculosis infection in contrast to WT or TLR-2/-4 DKO mice indicating that lack of IL-18 contributes to the high susceptibility of MyD88 KO mice to M. tuberculosis. Without IL-18, protective Th1 response was decreased and hence, mycobacterial propagation was favoured. Neutrophil-driven lung immunopathology concomitant with unrestrained growth of tubercle bacilli are most likely responsible for the premature death of IL-18 KO mice. Thus, IL-18 plays a decisive role in protective immunity against TB.

63: Vaccine, 2009 Nov 27, 389(4)
Adjuvant effects of chicken interleukin-18 in avian Newcastle disease vaccine.

[Abstract]Interleukin-18 (IL-18) can induce interferon-gamma (IFN-gamma) production and promote Th1 immunity, and hence, it modulates immune functions. In the present study, the in vitro and in vivo immunomodulatory activities of full length or mature chicken IL-18 expressed in a prokaryotic expression system (pCHIL18-F and pCHIL18-M, respectively) and chicken IL-18 expressed in a eukaryotic expression system (euCHIL18) were examined. Results showed that pCHIL18-F, pCHIL18-M and euCHIL18 significantly enhanced IFN-gamma mRNA expression in chicken splenocytes, which successfully increased IFN-gamma-induced nitric oxide (NO) synthesis by macrophages. Vaccination with cell-cultured Newcastle disease vaccine (NDTC) co-administrated with pCHIL18-F, pCHIL18-M or euCHIL18 resulted in significant increments of hemagglutination inhibition (HI) titers, cell proliferation of peripheral blood mononuclear cells (PBMC), and ratios of CD8(+) to CD4(+) in chickens compared with inoculation of PBS or NDTC alone. Thus, full length and mature chicken IL-18 expressed using a prokaryotic system and using a eukaryotic system showed equivalent in vitro and in vivo biological activities, and all forms effectively enhanced cell-mediated and humoral immunity, suggesting possible future use as a potential adjuvant in chicken NDTC vaccine production.

64: American journal of physiology. Cell physiology, 2009 Nov 11, 389(4)
Tumor Necrosis Factor-{alpha} Causes Release of Cytosolic Interleukin-18 from Human Neutrophils.

[Abstract]Objective: Neutrophils (PMNs) are a vital part of host defense and are the principal leukocyte in innate immunity. Interleukin-18 (IL-18) is a pro-inflammatory cytokine with roles in both innate and adaptive immunity. We hypothesize that PMNs contain preformed IL-18, which is released in response to specific inflammatory stimuli. Methods: Isolated PMNs were stimulated with a battery of chemoattractants (5 min to 24 hours), and IL-18 release was measured. PMNs were also separated into subcellular fractions and immunoblotted with antibodies against IL-18 or were fixed and probed with antibodies to IL-18 as well as to the contents of granules, intracellular organelles, and filamentous actin (f-actin), incubated with fluorescent secondary antibodies, and examined by digital microscopy. Results: Quiescent PMNs contained IL-18 in the cytoplasm, associated with f-actin, as determined by positive fluorescence resonance energy transfer (FRET+). In turn, TNFalpha stimulation disrupted the association of IL-18 with f-actin, induced a FRET+ interaction of IL-18 with lipid rafts, and elicited IL-18 release. Manipulation of f-actin status confirmed the relationship between IL-18 and f-actin in resting PMNs. Consequently, incubation with monomeric IL-18 binding protein inhibited TNFalpha-mediated priming of the PMN oxidase. Conclusion: Human PMNs contain IL-18 associated with f-actin in the cytoplasm, and TNFalpha stimulation causes dissociation of IL-18 from f-actin, association with lipid rafts, and extracellular release. Extracellular IL-18 participates in TNFalpha priming of the PMN oxidase as demonstrated by inhibition with the IL-18 binding protein.

65: BJOG : an international journal of obstetrics and gynaecology, 2009 Dec, 116(13)
Amniotic fluid interleukin-18 at mid-trimester genetic amniocentesis: relationship to intraamniotic microbial invasion and preterm delivery.

[Abstract]OBJECTIVE: To determine the value of amniotic fluid interleukin-18 (AF IL-18) in the diagnosis of microbial invasion of the amniotic cavity and prediction of preterm delivery (PTD). DESIGN: Analysis of the results of AF collected prospectively following genetic amniocentesis between February 2006 and September 2007. SETTING: A tertiary referral centre for fetal medicine. METHODS: Following amniocentesis, a sample of amniotic fluid was transferred to the laboratory for aerobic and anaerobic bacterial cultures, Ureaplasma urealyticum culture and IL-18 assays. All women who delivered preterm (<37 weeks of gestation) formed the study group. The control group consisted of the two subsequent women who also underwent amniocentesis during the same time period and delivered a normal neonate at term, matched for maternal age, parity and indication for amniocentesis. MAIN OUTCOME MEASURES: The relationship between AF IL-18 levels and the risk of both microbial invasion of the amniotic cavity and PTD. RESULTS: Forty-eight women who delivered preterm (<37 weeks) were matched with 96 controls. The preterm delivery group had significantly higher concentrations of IL-18 (median=609 pg/ml, interquartile range: 445.7-782.7) compared to controls (median=322.1 pg/ml, interquartile range: 277.7-414.4), (P<0.001). IL-18 level was also significantly higher (P<0.001) in cases with positive amniotic fluid cultures (median=697.7, interquartile range: 609.0-847.2) compared to those with negative ones (median=330.9 pg/ml, interquartile range: 235.2-440.8). CONCLUSIONS: Elevated mid-trimester concentrations of AF IL-18 can identify women at risk for intraamniotic infection and spontaneous PTD.

66: Metabolic syndrome and related disorders, 2009 Nov 9, 389(4)
The Effect of Exercise on Serum levels of Interleukin-18 and Components of the Metabolic Syndrome.

[Abstract]Background: There is increasing evidence that the metabolic syndrome is associated with a proinflammatory state. Interleukin-18 (IL-18) has been shown to be associated with multiple components of the syndrome and to predict the development of diabetes and cardiovascular events. The aim of the present work was to investigate if exercise could reduce serum levels of IL-18 in subjects with the metabolic syndrome, and if potential changes would be associated with changes in body composition and components of the syndrome. Pravastatin was used for comparison. Methods: We investigated the effect of 12 weeks of intervention with exercise, pravastatin, or both on serum levels of IL-18 in 34 subjects with the metabolic syndrome. Results: Levels of IL-18 were reduced by exercise (P = 0.036), pravastatin (P = 0.036), and the combination (P = 0.017) versus baseline, however without intergroup differences. Still, the reduction in the exercise group was not negligible (17.5%). Furthermore, reduced levels of IL-18 were significantly associated with improvement of an increasing number of components of the metabolic syndrome (P = 0.034). This effect is likely to be caused by exercise, because this intervention had a beneficial effect on components of the syndrome compared to the control group (P = 0.029). Conclusions: Our findings suggest that the protective effect of exercise might be due in part to reduced inflammation associated with improvement of the metabolic syndrome and its components. Studies with larger sample sizes are warranted to confirm this hypothesis.

67: Cytokine, 2009 Oct 29, 32(5)
TNFalpha and TGF-beta1 influence IL-18-induced IFNgamma production through regulation of IL-18 receptor and T-bet expression.

[Abstract]Bacterial infections can lead to a state of uncontrolled inflammation and also trigger autoimmune disease. At the centre of this are CD4(+) T cell responses in inflammatory tissues or local lymph nodes which are orchestrated by dendritic cells. IL-18 is a pro-inflammatory cytokine that drives dendritic cell maturation and mediates IFNgamma production. In this study, we demonstrate that in the dendritic precursor-like cell line KG-1, IFNgamma production induced by IL-18 is potentiated (>5-fold) by TNFalpha and completely suppressed by TGF-beta1. IL-18 stimulation rapidly activates different MAPK signalling pathways but only blocking of p38 activation alleviates IFNgamma production. The mechanism through which TNFalpha enhances IL-18 induced IFNgamma production is by promoting IL-18 receptor alpha-chain expression which results in higher levels of p38 activation and induces expression of T-bet, a transcriptional regulator of the IFNG gene. In contrast, TGF-beta1 rapidly suppresses IFNgamma production by limiting IL-18 receptor numbers at the cell surface and preventing induction of T-bet expression. TGF-beta1 experience by cells leads to sustained long-term inactivation of TNFalpha/IL-18-mediated cell activation but not IL-18 induced p38 activation suggesting transcriptional silencing of the T-BET and/or IFNG promoter independent of MAPK signalling. These results demonstrate how IL-18 activity is regulated by pro and anti-inflammatory cytokines and thereby provide insight into the mechanism that controls dendritic cell activity and ultimately leads to resolution of an inflammatory response.

68: Brazilian journal of medical and biological research = Revista brasileira de pesquisas m��dicas e biol��gicas / Sociedade Brasileira de Biof��sica ... [et al.], 2009 Nov, 42(11)
Peritoneal and serum interleukin-18 levels are not increased in women with minimum or mild endometriosis.

[Abstract]Interleukin-18 (IL-18) is a cytokine that belongs to the IL-1 family. Endometriosis is strongly associated with sub-fertility, and affects about 15% of women of reproductive age. IL-18 may favor the progression of endometriosis. The objective of the present study was to determine the concentration of IL-18 in the serum and peritoneal fluid of infertile women with endometriosis. Forty infertile and 25 fertile women were screened in a teaching hospital. Thirty-four infertile patients with minimal or mild endometriosis and 22 fertile controls were enrolled in the study. The primary outcome was the estimate of IL-18 levels and the secondary outcome was the correlation between serum and peritoneal levels of IL-18. There were no differences between the two groups regarding age, body mass index and levels of peritoneal fluid IL-18 (mean +/- SD): 290.85 +/- 173.02 pg/mL for infertile women vs 374.21 +/- 330.15 pg/mL for controls; or serum IL-18: 391.07 +/- 119.71 pg/mL for infertile women vs 373.42 +/- 129.11 pg/mL for controls. However, a positive association was found between serum and peritoneal IL-18 levels in patients with endometriosis: r = 0.794, P = 0.0001. All measurements were carried out at the same time by the Human IL-18 Immuno Assay ELISA kit (MBL Co. Ltd., Japan). The present study did not find evidence supporting the hypothesis that IL-18 levels are associated with infertility in women with minimal and mild endometriosis, although a positive correlation was detected in these women between peritoneal and serum levels of IL-18.

69: Atherosclerosis, 2009 Sep 25,
Arterial stiffness is independently associated with interleukin-18 and components of the metabolic syndrome.

[Abstract]

70: Haematologica, 2009 Oct 1, 106(41)
High dose dexamethasone regulates interleukin-18 and interleukin-18 binding protein in idiopathic thrombocytopenic purpura.

[Abstract]To evaluate the effects of high dose dexamethasone (HD-DXM) on the balance of interleukin-18 (IL-18) and its endogenous antagonist IL-18 binding protein (IL-18BP) in ITP patients, IL-18, IL-18BP as well as IFN-gamma,IL-4 plasma levels and platelets counts were determined in 17 ITP patients receiving DXM 40 mg/day for four consecutive days and in 24 healthy subjects. Using RT-PCR, the mRNA expression of IL-18, IL-18BP, IFN-gamma, IL-4, T-box (T-bet) and GATA-binding protein 3(GATA-3) were studied in all subjects. The in vitro effects of DXM on IL-18BP and IL-18 of peripheral blood mononuclear cells (PBMCs) were studied by ELISA. HD-DXM administration increased IL-18BP and reduced IL-18 expression significantly (p<0.05), which resulting in a downregulation of IL-18/IL-18BP ratio p<0.05). In vitro, DXM had a significant effect on secretion of IL-18BP while diminishing IL-18 release from cultures of PBMCs. These results suggest that downregulation of IL-18/IL-18BP might account for its clinical efficacy of HD-DXM in active ITP.

71: Biochemical and biophysical research communications, 2009 Nov 27, 389(4)
The dsRNA-mimetic poly (I:C) and IL-18 synergize for IFNgamma and TNFalpha expression.

[Abstract]Interleukin (IL)-18 bioactivity and dsRNA sensing by receptors of innate immunity are key components of anti-viral host defense. Despite extensive data on signal transduction activated by both pathways knowledge on cross-communication is incomplete. By using human PBMC and predendritic KG1 cells, as prototypic IL-18-responsive cellular models, we sought to assess cytokine production under the influence of IL-18 and the dsRNA-mimetic poly (I:C). Here, we report on potent synergy between both mediators concerning pro-inflammatory IFNgamma and TNFalpha production. KG1 data revealed that synergistic induction likely relied on TLR3 and was associated with prolonged/increased activation of NF-kappaB, as detected by IkappaB analysis and luciferase reporter assays, respectively. Moreover, extended activation of JNK was mediated by IL-18/poly (I:C). Although vital for innate immunity, overwhelming induction of inflammatory cytokines during viral infections poses the threat of serious collateral tissue damage. The stunning synergism inherent to IL-18/dsRNA-induced TNFalpha/IFNgamma detected herein may contribute to this pathological phenomenon.

72: Experimental dermatology, 2009 Sep 15, 389(4)
Serum levels of IL-18 and sIL-2R in patients with alopecia areata receiving combined therapy with oral cyclosporine and steroids.

[Abstract]Please cite this paper as: Serum levels of IL-18 and sIL-2R in patients with alopecia areata receiving combined therapy with oral cyclosporine and steroids. Experimental Dermatology 2009.Abstract: This study was to determine which immunologic factors contribute to the prognosis of patients with alopecia areata (AA) who were receiving oral cyclosporine A and methylprednisolone. Patients with >25% hair regrowth were defined as responders, and patients exhibiting 73: Annals of the New York Academy of Sciences, 2009 Sep, 1173(4)
IL-18 activity in systemic lupus erythematosus.

[Abstract]Interleukin-18 (IL-18) is an inflammation-related cytokine that plays a central role both in innate defense reactions and in Th1 activation and specific immune responses. Increased levels of IL-18 can be detected in biological fluids and organs of individuals affected by several autoimmune pathologies, as well as in autoimmune animal models. In this review, the role of IL-18 in systemic lupus erythematosus (SLE) is critically examined, including its possible role in the pathogenesis of disease. In SLE, increased levels of IL-18 have been found in serum/plasma of affected persons, which positively correlated with disease severity. The possibility that circulating IL-18 levels are predictive of renal damage has been proposed, suggesting that IL-18 may be a prognostic marker of renal involvement useful to identify patients at risk of renal failure. The evaluation of urinary levels of free active IL-18 indeed suggests a correlation with the degree of renal involvement. The possible pathogenic role of IL-18 in lupus has been studied in a mouse model of progressive disease, which makes possible the identification, at the level of the different affected organs, of IL-18 changes preceding disease development and those appearing after disease onset. It can be concluded that IL-18 has a multifaceted role in autoimmune lupus, being apparently involved both in the effector phases of the late organ damage and, in some organs, in the initial pathogenic events. Therapeutic strategies targeting IL-18 in autoimmunity are under development.

74: Digestive diseases and sciences, 2009 Sep 12, 1173(4)
A Functional SNP of the Interleukin-18 Gene Is Associated with the Presence of Hepatocellular Carcinoma in Hepatitis B Virus-Infected Patients.

[Abstract]BACKGROUND/AIM: The natural course of hepatitis B virus (HBV) infection is likely related to host immune factors. Interleukin-18 (IL-18) plays a significant role in immune defense. This study was undertaken to determine the association between the presence of hepatocellular carcinoma (HCC) and single-nucleotide polymorphisms (SNPs) in the IL-18 gene in HBV-infected patients. METHODS: Between March 2002 and December 2004, 730 Korean subjects were enrolled in two different groups: (1) chronic carrier without HCC (n = 637) and (2) HCC (n = 93). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions -667G>T, -148G>C, +8925C>G, and +13925A>C in the study subjects. To evaluate the functional significance of SNPs in the IL-18 gene promoter region, we performed a reporter gene assay in HepG2 and Hep3B cells transfected with different alleles. RESULTS: The IL-18 -148C allele, +8925G allele, +13925C allele, and haplotype 3 (TCGC) were associated with the presence of HCC in codominant and dominant models. Furthermore, functional analyses using the reporter gene assay revealed that the -148C allele conferred significantly lower promoter activity. CONCLUSIONS: This study indicates that the -148C, +8925G, and +13925C alleles of the IL-18 gene are associated with the presence of HCC and the 148G>C SNP is functionally important in determining disease outcome.

75: Cell biochemistry and biophysics, 2009 Sep 15, 1173(4)
Intermittent High Glucose Stimulate MCP-l, IL-18, and PAI-1, but Inhibit Adiponectin Expression and Secretion in Adipocytes Dependent of ROS.

[Abstract]Elevated circulating concentrations of interleukin-18 (IL-18), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) and decrease of adiponectin are associated with obesity-related diseases. The mechanism that mediates the aberrant production of the adipokines remains poorly understood. The aim of this study was to investigate the effect of intermittent high glucose on the expression of IL-18, MCP-1, and PAI-1 and adiponectin in 3T3-L1 adipocytes. 3T3-L1 adipocytes were incubated for 24 h in media containing different glucose concentrations: 5 mmol/l, 20 mmol/l and a daily alternating 5 or 20 mmol/l glucose, with or without the addition of 1.0 mmol/l N-acetylcysteine (NAC). The expression and secretion of IL-18, MCP-1, PAI-1, and adiponectin were determined by real-time RT-PCR and ELISA, respectively. The production of reactive oxygen species (ROS) and 8-hydroxydeoxyguanosine (8-OHdG) were measured. Stable high glucose significantly increased expression and secretion of IL-18, MCP-1, and PAI-1, and reduced adiponectin expression and secretion compared to normal glucose conditions. These effects were significantly greater under intermittent high glucose conditions compared to stable high glucose. The level of ROS and 8-OHdG were significantly elevated under both intermittent and stable high glucose conditions, the effect being greater under intermittent high glucose. The intermittent glucose was more effective in triggering the generation of ROS than stable high glucose. The adding of the NAC, a specific pharmacological inhibitor of ROS, normalized the expression of these adipokines and the levels of ROS and 8-OHdG under both stable and intermittent glucose conditions. Intermittent high glucose induces a greater aberrant production of key adipokines than stable high glucose, and this effect seems to be related to over-production of ROS.

76: American journal of respiratory and critical care medicine, 2009 Sep 10, 1173(4)
A Functional Polymorphism in IL-18 is Associated with Severity of Bronchial Asthma.

[Abstract]RATIONALE: Interleukin-18 (IL-18) is a unique cytokine that enhances innate immunity and both Th-1- and Th2-driven immune responses. Recent murine and human genetic studies have shown its role in the pathogenesis of asthma. OBJECTIVES: We conducted an association study in a Japanese population to discover variants of IL-18 that might have an effect on asthma susceptibility and/or progression and conducted functional analyses of the related variants. METHODS: The IL-18 gene locus was resequenced in 48 human chromosomes. Asthma severity was determined according to the 2002 GINA Guidelines. Association and haplotype analyses were performed using 1172 subjects. MEASUREMENTS AND MAIN RESULTS: Although no polymorphisms differed significantly in frequency between the control and adult asthma groups, rs5744247 C>G was significantly associated with the severity of adult asthma (steps 1, 2 vs. steps 3, 4; P = 0.0034). We also found a positive association with a haplotype (P = 0.0026). By in vitro functional analyses, the rs5744247 variant was found to increase enhancer-reporter activity of the IL-18 gene in bronchial epithelial cells. Expression levels of IL-18 in response to LPS stimulation in monocytes were significantly greater in subjects homozygous for the susceptibility G allele at rs5744247 C>G. Furthermore, we found a significant correlation between the serum IL-18 level and the genotype of rs5744247 (P = 0.031). CONCLUSIONS: Although the association results need to be replicated by other studies, IL-18 variants are significantly associated with asthma severity, and the rs5744247 variant reflects higher transcriptional activity and higher expression of IL-18 in LPS-stimulated monocytes and a higher serum IL-18 level.

77: Immunology, 2009 Sep, 128(1 Suppl)
Elevation of interleukin-18 in chronic hepatitis C: implications for hepatitis C virus pathogenesis.

[Abstract]The outcome of hepatitis C virus (HCV) infection is determined by the interplay between the virus and the host immune response. Interleukin (IL)-18, an interferon-gamma-inducing factor, plays a critical role in the T helper type 1 (Th1) response required for host defence against viruses, and antibodies to IL-18 have been found to prevent liver damage in a murine model. The present study was conducted to investigate the possible role of IL-18 in the pathogenesis and persistence of HCV. IL-18 levels were measured in sera of 50 patients at various stages of HCV infection (resolved, chronic and cirrhosis) and compared with those of normal controls. IL-18 gene expression was studied in peripheral blood mononuclear cells (PBMC) from each group, and in liver biopsy tissue from patients with chronic hepatitis C. The mean levels of IL-18 in sera were markedly elevated in patients with chronic hepatitis and cirrhosis, and were reduced in patients with resolved HCV infection. The serum IL-18 concentrations were related to the Child-Pugh severity of liver disease in cirrhotic patients. There also existed a strong positive correlation of IL-18 levels with histological activity score and necrosis. IL-18 mRNA expression was significantly up-regulated in the PBMC of cirrhotic patients when compared with other groups, while in the liver, higher levels of IL-18 transcripts were expressed in patients with chronic hepatitis C. The results of our study indicate that IL-18 levels reflect the severity and activity of HCV infection, and may contribute to the pathogenesis and progression of liver disease associated with HCV.

78: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2009, 30(4)
Immunotherapy with interleukin-18 in combination with preoperative chemotherapy with ifosfamide effectively inhibits postoperative progression of pulmonary metastases in a mouse osteosarcoma model.

[Abstract]The effect of immunotherapy with interleukin-18 (IL-18) in combination with preoperative chemotherapy on the postoperative progression of pulmonary metastasis was examined using a spontaneous pulmonary metastasis model of mouse osteosarcoma. Mice were inoculated subcutaneously with highly metastatic murine osteosarcoma cells (LM8) and then underwent chemotherapy with ifosfamide (30 or 60 mg/kg body weight, days 14-16), immunotherapy with IL-18 (2 microg/mouse, days 18-24) or combined immunotherapy and chemotherapy. Tumors developed in mice were excised 21 days after cell inoculation when microscopic but not macroscopic pulmonary metastasis was observed in mice. Three weeks after the excision of the tumors, macroscopic pulmonary metastasis was observed on the surface of the lung. Administration of ifosfamide or IL-18 alone decreased the number of macroscopic pulmonary metastases, and combined administration of ifosfamide and IL-18 resulted in much greater inhibition of pulmonary metastasis. These results suggest that immunotherapy in combination with preoperative chemotherapy is highly effective in suppressing postoperative progression of pulmonary metastasis.

79: Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2009 Jul, 25(7)
[The effect of IL-18 on E-cadherin expression and its possible intracellular pathway in HK-2 cells.]

[Abstract]AIM: To explore the effect of NF-kappaB signaling pathway in interleukin-18-induced transdifferentiation in renal proximal tubular cells. METHODS: In IL-18 stimulation groups, HK-2 cells were challenged with different concentrations (0, 1, 10, 100 mug/L) of IL-18 for 72 h; In SN50 preincubation groups, HK-2 cells were incubated with 100 mg/L SN50 for 30 min before IL-18 was added. At the end of the incubation, the expression of E-cadherin was determined by the combination of immunocytochemistry and RT-PCR. RESULTS: Percentage of E-cadherin positive expression HK-2 cells was decreased by IL-18 in dosage dependant manner. Expression of E-cadherin mRNA in HK-2 cells was also decreased by IL-18 in dosage dependant manner. Recovered the mostly part of expression of E-cadherin was found after HK-2 cells were pretreated with SN50. CONCLUSION: IL-18-induced transdifferentiation of RTECs is suppressed by blocking NF-kappaB signaling pathway. IL-18-induced transdifferentiation of RTECs at least is partly via NF-kappaB pathway.

80: Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2009 Jul, 25(7)
[Inhibitory effect of triptolide on interleukin-18 and its receptor in rheumatoid arthritis synovial fibroblasts.]

[Abstract]AIM: To determine the effects of triptolide (TP) on the expression of interleukin-18 (IL-18) and its receptor in phorbol 12-myristate 13-acetate (PMA)-stimulated rheumatoid arthritis synovial fibroblasts (RASF). METHODS: RASF were pretreated with TP (0-100 mug/L) for 2 h before stimulation with PMA (50 mug/L). The bioactivity of IL-18 in the supernatant was detected based on IFN-gamma secretion from IL-18-responding human myelomonocytic KG-1 cells. IL-18 level was analyzed by ELISA. To estimate the protein and mRNA expression of IL-18 and IL-18Ralpha in RASF, Western blot and quantitative RT-PCR were performed. Nuclear factor-kappaB (NF-kappaB) activity in the whole-cell extract of treated RASF was also measured using an ELISA-based method. RESULTS: TP effectively inhibited the bioactivity of IL-18 in PMA-stimulated RASF. The expression of IL-18 and IL-18R at protein and gene levels was reduced by TP. NF-kappaB activity in PMA-stimulated RASF was profoundly suppressed by TP. These effects showed a high correlation with TP concentration (0-100 mug/L). CONCLUSION: TP effectively inhibited the expression of IL-18 and its receptor in PMA-stimulated RASF. These results suggest a mechanism of TP in RA therapy.

81: FEMS immunology and medical microbiology, 2009 Nov, 57(2)
Cloning, in vitro expression, and bioactivity of interleukin-18 isolated from a domestic porcine breed found in Henan.

[Abstract]To evaluate the effects of recombinant porcine interleukin-18 (rpIL-18) on the replication of viruses in host cells and proliferation of lymphocytes, porcine IL-18 (pIL-18) isolated from a domestic big-white porcine breed found in the Henan province (HN) was cloned using a reverse transcriptase-PCR. The cloned HN pIL-18 contained an ORF of 579 base pairs encoding a 192-amino-acid precursor protein. The amino acid sequence of HN pIL-18 was compared with all the other pIL-18 amino acid sequences and varied by at least one amino acid to the consensus of all the others available. HN pIL-18 mature protein gene was inserted into a prokaryotic vector pGEX-4T-1 and expressed in Escherichia coli BL21. The expression of glutathione-S-transferase-pIL18 fusion protein was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis. The rpIL-18 induced in vitro proliferation of concanavalin-A-stimulated porcine splenocytes, as revealed by the MTT assay. We studied the antiviral activities of the rpIL-18 on the replication of porcine reproductive and respiratory syndrome virus (PRRSV), pseudorabies virus (PRV), and porcine parvovirus (PPV) cultured in two homologous cell lines. The results suggested that rpIL-18 can stimulate the proliferation of lymphocytes and inhibit viral pathogens infecting the porcine population.

82: Behavioural brain research, 2010 Jan 5, 206(1)
Interleukin-18 regulates motor activity, anxiety and spatial learning without affecting synaptic plasticity.

[Abstract]Expression of Schaffer collateral-CA1 long-term potentiation (LTP) and long-term depression (LTD) was not affected in hippocampal slices from wild-type mice pretreated with lipopolysaccharide (0.25mg/kg, i.p.), to increase interleukin-18 (IL-18) concentrations in the brain. For IL-18 knock-out (IL-18 KO) mice, the LTP was still expressed, the extent being similar to that for wild-type mice. In the open-field test to assess motor activity, rearing activity for IL-18 KO mice was significantly suppressed as compared with that for wild-type mice, without significant difference in the locomotion activity between two groups. In the passive avoidance test to assess fear memory, the retention latency for IL-18 KO mice was much shorter than for wild-type mice, without significant difference in the acquisition latency between two groups. In the water maze test, the acquisition latency for IL-18 KO mice significantly prolonged as compared with that for wild-type mice, without significant difference in the retention latency between two groups. For IL-18 KO mice, intraventricular injection with IL-18 for 4 days (total, 240 fg) prior to water maze task shortened the prolonged acquisition latency, reaching a level similar to that for wild-type mice. The results of the present study, thus, suggest that IL-18 is a critical regulator for exploratory activity, fear memory, and spatial learning.

83: Atherosclerosis, 2010 Feb, 208(2)
IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome.

[Abstract]Although considerable evidence implicates the cytokine interlukin-18 (IL-18) in metabolic syndrome (MetS), the direct effect of IL-18 on vascular changes of MetS remains unknown. We investigated the chronic in vivo effect of IL-18 on development of MetS and vascular inflammation and remodeling by overexpressing IL-18 protein in fructose-fed rats (FFR), a model of MetS using intravenous administration of an adenovirus encoding rat IL-18. Increased serum IL-18 and vascular inflammatory response were found in FFR. Overexpression of IL-18 aggravated insulin resistance and enhance vascular inflammation and remodeling, which can be reflected by increased aortic expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and enhanced infiltration of macrophages and increased aortic wall thickness and wall-to-lumen ratio. Interestingly, the levels of interleukin-1 receptor-associated kinase 1 (IRAK1) and the activity of nucleus factor-kappaB (NF-kappaB) were also significantly increased. Together, these results indicated that chronic elevated IL-18 levels at a supraphsiological concentration aggravated insulin resistance, enhanced vascular inflammation and remodeling, probably by increasing the level of IRAK1 and the activity of NF-kappaB. Targeting expression of IL-18 or its specific downstream mediators may retard the progression of MetS and its complications.

84: Journal of autoimmunity, 2010 Mar, 34(2)
High circulating levels of free interleukin-18 in patients with active SLE in the presence of elevated levels of interleukin-18 binding protein.

[Abstract]Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies particularly to nuclear antigens and by an abnormal production of proinflammatory cytokines. In the present study, we measured the levels of the proinflammatory cytokine IL-18 and its natural inhibitor, the IL-18 binding protein (IL-18BP), in sera of SLE patients at various stages of the disease. This is the first study to present IL-18BP levels in sera of SLE patients as well as the calculated, biologically active, free IL-18 concentrations that are most probably more relevant to the pathology of SLE. Sera from 48 unselective SLE patients (total of 195 samples) were obtained longitudinally with a mean follow-up period of 11.1 +/- 8.9 years and were compared to sera from 100 healthy volunteers. Circulating levels of IL-18, IL-18BP and free IL-18 in the SLE patients were significantly higher than the levels of healthy controls (5 fold, 6 fold and 3 fold for IL-18, IL-18BP and free IL-18, respectively) and correlated with disease activity as scored by SLEDAI-2K. Furthermore, these levels during active disease (SLEDAI-2K >/= 6) were higher compared to the levels measured in the sera of the same patients during remission or during mild disease (SLEDAI-2K 0-5). The high levels of IL-18 and IL-18BP in sera of active SLE patients suggest their possible role in the pathogenesis and course of the disease. However, despite the elevated levels of IL-18BP during active disease, free IL-18 remained more than 2 fold higher than the levels in healthy controls suggesting a potential benefit of administration of exogenous IL-18BP as a novel therapeutic approach for active SLE.

85: Obesity (Silver Spring, Md.), 2010 Mar, 18(3)
Effect of Diet-induced Obesity on Acute Pancreatitis Induced by Administration of Interleukin-12 Plus Interleukin-18 in Mice.

[Abstract]Obesity is associated with increased severity of acute pancreatitis (AP). We recently developed a model of AP induced by administration of interleukin (IL)-12+IL-18, two cytokines that are elevated in patients with AP. In this model, severe AP develops in obese leptin-deficient ob/ob mice compared to lean littermates. In the present report, we evaluated the pancreatic response of diet-induced obesity (DIO) mice to IL-12+IL-18. Body weight loss and adipose tissue necrosis were more severe and prolonged in cytokine-injected DIO compared to lean mice. Edematous AP developed in lean mice, whereas DIO mice developed necrotizing AP. Obese DIO mice developed more severe hypocalcemia, increased liver damage and a heightened acute-phase response compared to lean mice, although leukopenia and thrombocytopenia were of comparable severity in lean and DIO mice. Serum levels of IL-6, IL-10, and IL-22 were significantly higher in DIO compared to lean mice, whereas interferon-gamma and tumor necrosis factor-alpha did not differ between the two groups. In conclusion, obesity induced by high-fat diet is associated with increased disease severity and duration in the model of AP induced by administration of IL-12+IL-18.

86: The Journal of investigative dermatology, 2010 Jan, 130(1)
Contrasting Roles of the IL-1 and IL-18 Receptors in MyD88-Dependent Contact Hypersensitivity.

[Abstract]Contact hypersensitivity (CHS) requires activation of the innate immune system, and results in an adaptive immune response. Many cells of the innate immune system use Toll-like receptors (TLRs), which signal through the adaptor protein, MyD88, to initiate an immune response. MyD88 is also required for signaling downstream of the IL-1 and Il-18 receptors (IL-1R and IL-18R, respectively). Herein, we studied the MyD88 signaling pathway in the CHS response to DNFB. Mice deficient in MyD88 were unable to mount a CHS response to DNFB. In contrast, mice deficient in Toll/IL-1R-containing adaptor-inducing IFN-beta, TLR2, TLR4, TLR6, and TLR9 had no defect in their ability to respond to DNFB. Although both IL-1R and IL-18R-deficient mice showed a reduced CHS response to DNFB, in bone marrow chimera and adoptive transfer experiments, we found that MyD88 and the IL-18R were required in a radioresistant cell in the sensitization phase of the CHS response. In contrast, similar strategies revealed that the IL-1R was required in a radiosensitive cell in the sensitization phase of the CHS response. Taken together, these data indicate that the IL-1R and IL-18R/MyD88 pathways are required in distinctly different cells during the sensitization phase of CHS.

87: Journal of neuroimmunology, 2009 Sep 29, 214(1-2)
Mapping of the full length and the truncated interleukin-18 receptor alpha in the mouse brain.

[Abstract]The cytokine IL-18 acts on the CNS both in physiological and pathological conditions. Its action occurs through the heterodimeric receptor IL-18Ralpha\beta. To better understand IL-18 central effects, we investigated in the mouse brain the distribution of two IL-18Ralpha transcripts, a full length and an isoform lacking the intracellular domain hypothesized to be a decoy receptor. Both isoforms were expressed in neurons throughout the brain primarily with overlapping distribution but also with some unique pattern. These data suggest that IL-18 may modulate neuronal functions and that its action may be regulated through expression of a decoy receptor.

88: Carcinogenesis, 2009 Dec, 30(12)
Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44.

[Abstract]Cancer cells metastasize to the other site after escaping from the immune system and CD70, CD44 and vascular endothelial growth factor (VEGF) play important roles in this process. It is recently reported that interleukin (IL)-18 is closely related with the pathogenesis of skin tumor. Therefore, we investigated the role of endogenous IL-18 from stomach cancer on the immune escape mechanism and metastasis via the regulation of CD70, CD44 and VEGF expression. IL-18 and IL-18R expressions were not only investigated on tumor tissues (n = 10), and sera (n = 20) from stomach cancer patients, but also on human stomach cancer cell lines. IL-18 and IL-18R expressions were found on stomach cancer cell lines and tumor tissues. In addition, IL-18 levels were elevated in sera from cancer patients (P < 0.05), compared with sera from normal individuals. Changes in CD70, CD44 and VEGF expression by flow cytometry, immunoblotting and enzyme-linked immunosorbent assay and immune susceptibility by (51)Cr-release assay were investigated, after silencing or neutralization of endogenous IL-18. CD70 expression was increased and it increases immune susceptibility of cancer cells. In contrast, CD44 and VEGF expression was decreased and it suppresses neovascularization and the metastasis of stomach cancer. After inoculation of IL-18 small interfering RNA (siRNA)-transfected stomach cancer cells into Balb/C (nu/nu) mice, regression of tumor mass was determined by measuring of tumor size. And the number and location of metastatic lesions were investigated by hematoxylin and eosin staining. The regression of tumor mass and the suppression of metastasis were observed in the mice, which are injected with IL-18 siRNA-transfected cell lines. Our data suggest that endogenous IL-18 might facilitate stomach cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF.

89: The journals of gerontology. Series A, Biological sciences and medical sciences, 2009 Nov, 64(11)
Interleukin-18 polymorphism and physical functioning in older people: a replication study and meta-analysis.

[Abstract]BACKGROUND: Levels of the proinflammatory cytokine interleukin-18 (IL-18) are raised in old age and are associated with reduced physical functioning. Previous studies have indicated that the C allele of the rs5744256 polymorphism in the IL-18 gene is strongly associated with reduced circulating IL-18 levels. This variant has previously been associated with improved locomotor performance in old age, but the finding requires independent replication. METHODS: We examined the association between the IL-18 polymorphism rs5744256 and physical functioning in three cohorts with a total of 4,107 participants aged 60-85 years: the English Longitudinal Study of Ageing, Caerphilly, and Boyd Orr. We meta-analyzed (N = 6,141) the results with data from the original paper reporting this association: Iowa-Established Populations for Epidemiological Study of the Elderly and InCHIANTI cohorts. Physical functioning was assessed by timed walks or the get up and go test. As locomotor performance tests differed between the cohorts and the distributions of times to complete the test (in seconds) were positively skewed, we used the reciprocal transformation and computed study-specific z scores. RESULTS: Based on the three new studies, the estimated linear regression coefficient per C allele was 0.011 (95% confidence interval [95% CI]: -0.04 to 0.06). A meta-analysis that pooled the data from all studies showed weak evidence of an effect, with a regression coefficient of 0.047 (95% CI: 0.010 to 0.083). CONCLUSIONS: We did not replicate an association between the IL-18 rs5744256 polymorphism and the physical function in people aged 60-85 years. However, pooling data from all studies suggested a weak association of the C allele of the rs5744256 single nucleotide polymorphism on improving walking times in old age.

90: Metabolism: clinical and experimental, 2009 Nov, 58(11)
Serum levels of interleukin-18 are reduced by diet and n-3 fatty acid intervention in elderly high-risk men.

[Abstract]Inflammation plays a central role in the development and progression of atherosclerosis, and inflammatory markers have been reported to predict cardiovascular events. Mediterranean-like diet and very long chain omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation have been reported to reduce the risk of cardiovascular mortality and morbidity, but the mechanisms are not fully clarified. The aims of the present study were to investigate the effect of such interventions on serum levels of inflammatory markers, and potential associations with changes in serum fatty acids and anthropometric measures. This was a randomized 2 x 2 factorial-designed trial comparing the effect of 3 years of dietary counseling, n-3 PUFA supplementation (2.4 g/d), or both on different measures of atherosclerosis in elderly high-risk men (N = 563). Levels of interleukin-18 (IL-18) were decreased by diet (-10.5% vs baseline, P = .012 compared with no diet) and by n-3 PUFA supplementation (-9.9% vs baseline, P = .008 compared with placebo). Other measured inflammatory markers were not affected. Changes in IL-18 were significantly correlated to changes in triglycerides (r = 0.20, P < .001), eicosapentaenoic acid (r = -0.14, P = .030), docosahexaenoic acid (r = -0.14, P = .034), body mass index (r = 0.16, P < .001), and waist circumference (r = 0.12, P = .007). In conclusion, levels of IL-18 were significantly reduced by Mediterranean-like diet and n-3 PUFA supplementation. However, the changes correlated only weakly to changes in triglycerides, serum fatty acids, and anthropometric measures. The cardioprotective effects of both interventions might thus in part be explained by reduced levels of IL-18, but probably beyond changes in serum fatty acids and body composition.

91: The Journal of biological chemistry, 2009 Sep 18, 284(38)
Increased cytokine production in interleukin-18 receptor alpha-deficient cells is associated with dysregulation of suppressors of cytokine signaling.

[Abstract]Since interleukin (IL)-18 is a proinflammatory cytokine, mice lacking IL-18 or its ligand-binding receptor (IL-18R) should exhibit decreased cytokine and chemokine production. Indeed, production of IL-1alpha, IL-6, and MIP-1alpha was reduced in IL-18 knock-out (ko) mouse embryonic fibroblast (MEF)-like cells. Unexpectedly, we observed a paradoxical 10-fold increase in IL-1beta-induced IL-6 production in MEF cells from mice deficient in the IL-18R alpha-chain (IL-18Ralpha) compared with wild type MEF. Similar increases were observed for IL-1alpha, MIP-1alpha, and prostaglandin E2. Likewise, coincubation with a specific IL-18Ralpha-blocking antibody augmented IL-1beta-induced cytokines in wild type and IL-18 ko MEF. Stable lines of IL-18Ralpha-depleted human A549 cells were generated using shRNA, resulting in an increase of IL-1beta-induced IL-1alpha, IL-6, and IL-8 compared to scrambled small hairpin RNA. In addition, we silenced IL-18Ralpha with small interfering RNA in primary human blood cells and observed up to 4-fold increases in the secretion of lipopolysaccharide- and IL-12/IL-18-induced IL-1beta, IL-6, interferon-gamma, and CD40L. Mechanistically, despite increases in Stat1 and IL-6, induction of SOCS1 and -3 (suppressor of cytokine signaling 1 and 3) was markedly reduced in the absence of IL-18Ralpha. Consistent with these observations, activation of the p38alpha/beta and ERK1/2 MAPKs and of protein kinase B/Akt increased in IL-18Ralpha ko MEF, whereas the negative feedback kinase MSK2 was more active in IL-18 ko cells. These data reveal a role for SOCS1 and -3 in the seemingly paradoxical hyperresponsive state in cells deficient in IL-18Ralpha, supporting the concept that IL-18Ralpha participates in both pro- and anti-inflammatory responses and that an endogenous ligand engages IL-18Ralpha to deliver an inhibitory signal.

92: Respiratory medicine, 2009 Dec, 103(12)
IL-18 in induced sputum and airway hyperresponsiveness in mild asthmatics: effect of smoking.

[Abstract]Interleukin 18 (IL-18) is a pro-inflammatory cytokine, which has been shown to be implicated in the induction of airway hyperresponsiveness (AHR) in murine asthma models. The association of IL-18 with AHR in human bronchial asthma is not clear as yet. As cigarette smoking modifies airway inflammation we aimed to assess the relationship of IL-18 with airway hyperresponsiveness (AHR) in non-smoking versus smoking asthmatics. IL-18 was measured in sputum supernatants obtained from asthmatic (24 smokers and 22 non-smokers) and healthy subjects (16 smokers and 17 non-smokers). All subjects were assessed by spirometry, skin-prick tests to common aeroallergens and bronchial provocation to methacholine (Mch). There was no significant difference in IL-18 levels between healthy and asthmatic smokers and between healthy and asthmatic non-smokers. IL-18 levels in sputum were significantly lower in healthy smokers compared to non-smokers (p=0.048); similarly, in asthmatic smokers as compared to non-smokers (p=0.037). An inverse correlation was found between IL-18 levels, FEV(1) (% pred) (r=-0.495, p=0.043), and PD(20)Mc(h) in non-smoking asthmatics (r=-0.621, p=0.024). A positive correlation was found in smoking asthmatics between IL-18 levels in sputum and FEV(1) (% pred) (r=0.627, p=0.002), FVC (% pred) (r=0.460, p=0.031), and PD(20)Mc(h) (r=0.809, p=0.005). Cigarette smoking reduced IL-18 levels in induced sputum in healthy and asthmatic smokers. IL-18 levels were correlated with airway obstruction and AHR in an inverse way in smoking and non-smoking asthmatics. These results suggest the implication of IL-18 in airway hyperresponsiveness characterizing bronchial asthma, which is modified by smoking.

93: Cancer letters, 2009 Dec 28, 286(2)
Interleukin-18 induces transferrin expression in breast cancer cell line MCF-7.

[Abstract]Interleukin-18 (IL-18) has recently been shown to have a pro-cancer effect in various cancers. Increased serum levels of both IL-18 and transferrin in cancer patients are correlated with its malignancy. However, the relationship between transferrin and IL-18 is not well understood. Here, we show that exogenous transferrin enhanced breast cancer cell proliferation and the proliferation rate was reduced when endogenous transferrin expression was inhibited by transferrin siRNA. The expression of endogenous transferrin was found to be regulated by IL-18. Furthermore, we found that the MAPK pathway is involved in IL-18-induced transferrin production. In conclusion, IL-18 is suggested as an inducer of endogenous transferrin expression in breast cancer cells.

94: Cancer gene therapy, 2010 Jan, 17(1)
Oncolytic adenovirus expressing interleukin-18 induces significant antitumor effects against melanoma in mice through inhibition of angiogenesis.

[Abstract]It has been shown that interleukin 18 (IL-18) exerts antitumor activity. In this study, we investigated whether oncolytic adenovirus-mediated gene transfer of IL-18 could induce strong antitumor activity. A tumor-selective replicating adenovirus expressing IL-18 (ZD55-IL-18) was constructed by insertion of an IL-18 expression cassette into the ZD55 vector, which is based on deletion of the adenoviral E1B 55-kDa gene. It has been shown that ZD55-IL-18 exerted a strong cytopathic effect and significant apoptosis in tumor cells. ZD55-IL-18 significantly decreased vascular endothelial growth factor and CD34 expression in the melanoma cells. Treatment of established tumors with ZD55-IL-18 showed much stronger antitumor activity than that induced by ZD55-EGFP (enhanced green fluorescent protein) or Ad-IL-18. These data indicated that oncolytic adenovirus expressing IL-18 could exert potential antitumor activity through inhibition of angiogenesis and offer a novel approach to melanoma therapy.

95: Digestive diseases and sciences, 2010 Apr, 55(4)
Association of interleukin-18 gene polymorphisms with hepatitis B virus clearance.

[Abstract]The outcome of hepatitis B virus (HBV) infection can be affected by host immune factors. Interleukin-18 (IL-18) was originally discovered as an interferon-gamma-inducing factor and plays a critical role in immune response. We assessed the association between the clearance of HBV infection and single-nucleotide polymorphisms (SNPs) in the IL-18 gene. Between March 2002 and December 2004, a total of 1,050 Korean subjects were enrolled in the study and divided into two groups: (1) the HBV spontaneous recovery group (n = 320) and (2) the chronic HBV carrier group (n = 730). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions -667G>T, -148G>C, +8925C>G, and +13925A>C. We observed that the subjects bearing the IL-18 -148C allele [odds ratio (OR), 0.25; confidence interval (CI), 0.09-0.68; P = 0.01], the +8925G allele (OR, 0.36; CI, 0.15-0.88; P = 0.02), and the +13925C allele (OR, 0.25; CI, 0.13-0.82; P = 0.01) were significantly associated with HBV clearance in a recessive model. This study indicates that the -148C, +8925G, and +13925C alleles of the IL-18 gene are likely associated with HBV clearance in a Korean population.

96: Journal of the European Academy of Dermatology and Venereology : JEADV, 2010 Jan, 24(1)
Association of single nucleotide polymorphism of interleukin-18 with atopic dermatitis.

[Abstract]It has been shown that interleukin 18 (IL-18) exerts antitumor activity. In this study, we investigated whether oncolytic adenovirus-mediated gene transfer of IL-18 could induce strong antitumor activity. A tumor-selective replicating adenovirus expressing IL-18 (ZD55-IL-18) was constructed by insertion of an IL-18 expression cassette into the ZD55 vector, which is based on deletion of the adenoviral E1B 55-kDa gene. It has been shown that ZD55-IL-18 exerted a strong cytopathic effect and significant apoptosis in tumor cells. ZD55-IL-18 significantly decreased vascular endothelial growth factor and CD34 expression in the melanoma cells. Treatment of established tumors with ZD55-IL-18 showed much stronger antitumor activity than that induced by ZD55-EGFP (enhanced green fluorescent protein) or Ad-IL-18. These data indicated that oncolytic adenovirus expressing IL-18 could exert potential antitumor activity through inhibition of angiogenesis and offer a novel approach to melanoma therapy.

97: Journal of leukocyte biology, 2009 Oct, 86(4)
IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway.

[Abstract]IL-4 and IL-13 are instrumental in the development and progression of allergy and atopic disease. Basophils represent a key source of these cytokines and produce IL-4 and IL-13 when stimulated with IL-18, a member of the IL-1 family of cytokines. Comparative analyses of the effects of caspase-1-dependent IL-1 family cytokines on basophil IL-4 and IL-13 production have not been performed, and the signaling pathway proteins required for FcepsilonRI-independent Th2 cytokine production from basophils remain incompletely defined. Using mouse bone marrow-derived cultured basophils, we found that IL-4 and IL-13 are produced in response to IL-18 or IL-33 stimulation. IL-18- or IL-33-mediated Th2 cytokine production is dependent on MyD88 and p38alpha signaling proteins. In addition, basophil survival increased in the presence of IL-18 or IL-33 as a result of increased Akt activation. Studies in vivo confirmed the potency of IL-18 and IL-33 in activating cytokine release from mouse basophils.

98: The Journal of surgical research, 2010 Jan, 158(1)
Interleukin-18 Exacerbates Pulmonary Injury after Hepatic Ischemia/Reperfusion in Mice.

[Abstract]BACKGROUND: Hepatic ischemia/reperfusion has been shown to cause both local hepatic and distant organ (such as lung) injury caused by accumulation of neutrophils in the local and distant organs, leading to neutrophil-dependent organ injury. Interleukin (IL) -18 is required for facilitating neutrophil-dependent local hepatic injury by suppressing anti-inflammatory cytokine expression, but less is known about the involvement of this cytokine in distant organ injury. The objective of this study was to determine whether IL-18 contributes to pulmonary injury induced by hepatic ischemia/reperfusion. METHODS: C57BL/6 mice and IL-18 knockout mice (C57BL/6 background) were subjected to 90 min of partial hepatic ischemia and subsequent reperfusion. Neutrophil accumulation in the lung was assessed by pulmonary myeloperoxidase contents. Pulmonary expressions of keratinocyte derived chemokine (KC, CXCL1), macrophage chemoattractant protein-1 (MCP-1, CCL2), tumor necrosis factor-alpha, interferon-gamma, IL-4, and IL-10 were measured by tissue enzyme-linked immunosorbent assay (ELISA). Lung edema was quantified by the pulmonary wet to dry weight ratios. RESULTS: Hepatic ischemia/reperfusion caused significant increases in pulmonary neutrophil recruitment and lung edema. Also, pulmonary expression of KC and MCP-1 were up-regulated. In the IL-18 knockout mice, hepatic ischemia/reperfusion-induced increases in pulmonary neutrophil recruitment, lung injury defined by lung edema, and pulmonary chemokine expression were attenuated. Furthermore, pulmonary expression of an anti-inflammatory cytokine IL-4 and systemic IL-10 expression were significantly up-regulated in the IL-18 knockout mice. CONCLUSIONS: The data suggested that IL-18 plays an important role in the development of pulmonary injury after hepatic ischemia/reperfusion by up-regulating proinflammatory mediators and possibly suppressing anti-inflammatory cytokine expression.

99: Molecular biology reports, 2009 Nov, 36(8)
Interleukin-18 gene promoter and serum level in women with ovarian cancer.

[Abstract]IL-18, initially defined as a potent inducer of IFN- gamma production, is a systemic, multifunctional cytokine with both pro-cancerous and anti-cancer activities. The contribution of the IL-18 promoter polymorphisms at positions -607 (C/A) and -137 (G/C) to cancer development has been reported. We sought to examine IL-18 serum level and its polymorphisms in Iranian women with ovarian cancer. Single nucleotide polymorphisms (SNPs) at positions -607 (C/A) and -137 (G/C) were analyzed by allele-specific polymerase chain reaction in 85 women with ovarian cancer and 158 healthy controls. IL-18 serum level was determined using ELISA method. No significant association was found between the allele, genotype, and haplotype distributions of the SNPs and ovarian cancer. Mean IL-18 serum level was significantly higher in patients than in controls (P = 0.008). Comparing IL-18 serum levels with genotypes at positions -607 and -137 revealed no significant difference. No association was also found between IL-18 levels and the disease stage. In conclusion, our results indicate that IL-18 promoter polymorphisms at positions -607 (C/A) and -137 (G/C) appear not to confer susceptibility to ovarian cancer in Iranian population; however, IL-18 serum level increases in ovarian cancer patients.

100: Clinical and experimental medicine, 2009 Feb 24, 59 Suppl 6
Proapoptotic IL-18 in patients with chronic hepatitis C treated with pegylated interferon-alpha.

[Abstract]Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. In mainland of China, It was estimated the population of 1.3 billion infected with HCV. HCV is not cytopathic. Immune response that is essentially conducted by cytokines may play an important role in the pathogenesis of HCV infection. Interleukin (IL)-18, mainly produced by monocytes/macrophages, plays an important role in the immune system by enhancing T cell responses, regulating interferon-gamma (IFN-gamma) production and promoting the development of T helper cell Th1 immune responses. Raised serum levels of IL-18 have recently been reported in patients with chronic hepatitis C before antiviral therapy. Herein we report the IL-18 sequential changes in patients with hepatitis C during the period of pegylated interferon (PEG-IFN) alpha treatment for 48 weeks. We established the correlation of plasma IL-18 level and alanine aminotransferase (r = 0.77, P < 0.05). Hepatic inflammatory activity in chronic hepatitis C was shown to be closely associated with an increased amount of IL-18. HCV-infected patients had raised IL-18 levels (93.67 +/- 23.58 pg/ml versus 59.73 +/- 24.06 pg/ml; P < 0.001) comparing donor negativity for HCV. PEG-IFN alpha-2a treatment induces a marked decline in IL-18 and remission of hepatic inflammatory in responders at week 24 and week 48 follow-up time point, while increased levels persist in those in whom the HCV infection was not eliminated by the therapy. We proposed declined IL-18 levels favor for virus solution, while persistent raised IL-18 associated with PEG-IFN treatment failure.

101: Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology, 2009 Feb, 17(1)
[Serum Levels of sVCAM-1, IL-18 and VEGF in Patients with Aplastic Anemia and Their Clinical Significance.]

[Abstract]This study was purposed to investigate the serum levels of soluble intracellular adhesion molecule (sVCAM-1), interleukin 18 (IL-18) and vascular endothelial growth factor (VEGF) in patients with aplastic anemia (AA) and their clinical significance. Enzyme linked immunosorbent assay (ELISA) was used to detect sVCAM-1, IL-18 and VEGF in serums of 30 patients with AA and 25 normal controls. The results showed that the serum levels of sVCAM-1 and IL-18 in patients with AA [(839.08 +/- 173.97) ng/ml, (380.35 +/- 47.76) pg/ml] were significantly higher than those in normal controls [(538.16 +/- 91.21) ng/ml, (256.39 +/- 59.52) pg/ml] (p < 0.01; p < 0.01). The levels of sVCAM-1 and IL-18 in severe AA patients [(969.94 +/- 182.54) ng/ml, (388.96 +/- 46.06) pg/ml] were higher than those in chronic AA patients [(709.26 +/- 165.32) ng/ml, IL-18 (352.21 +/- 47.08) pg/ml] (p < 0.01; p < 0.05), but the level of VEGF in AA patients [(69.63 +/- 27.42) pg/ml] was lower than that in the normal controls [(125.62 +/- 32.15) pg/ml] (p < 0.01)]. The level of VEGF in severe AA patients [(51.30 +/- 29.86) pg/ml] was significantly lower than that in chronic AA patients [(80.02 +/- 25.14) pg/ml] (p < 0.01). The levels of sVCAM-1 and IL-18 in AA patients after treatment were lower than those before treatment (p < 0.01; p < 0.05), but the level of VEGF after treatment was significantly higher than that before treatment (p < 0.05). It is concluded that the high levels of sVCAM-1, IL-18 and low level of VEGF in serum may be involved in the pathogenesis and progress of AA.

102: Nature clinical practice. Cardiovascular medicine, 2009 Mar, 6(3)
The role of interleukin 18 in the pathogenesis of hypertension-induced vascular disease.

[Abstract]Understanding the mechanism by which chronic high blood pressure induces vascular disease is of fundamental importance for prevention of the adverse consequences of hypertension. Clinical and population studies have consistently found increased circulating levels of interleukin 18 (IL-18) in patients with hypertension. Although obesity, and possibly age, is a determinant of plasma IL-18 levels, the relationship of IL-18 to hypertension seems to be independent of these factors. Experimental evidence indicates that the expression of IL-18 and/or its receptor can be induced by catecholamines or angiotensin, two factors that are involved in the pathophysiology of hypertension. Elevated circulating IL-18 levels are associated with vascular changes in the carotid artery, including increased carotid intima-media thickness, which, in turn, is a predictor of cardiovascular events in patients with established coronary disease. IL-18, either directly or through oxidative stress pathways and matrix metalloproteins, can alter endothelial function or induce vascular smooth muscle cell migration and/or proliferation to produce the vascular changes that occur with hypertension. This Review examines the data on IL-18 and hypertensive vascular disease, and explores the potential cellular and molecular mechanisms that might connect hypertension to vascular disease.

103: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology, 2009 Feb, 102(2)
Interleukin 12, interleukin 18, and tumor necrosis factor alpha release by alveolar macrophages: acute and chronic hypersensitivity pneumonitis.

[Abstract]BACKGROUND: Hypersensitivity pneumonitis (HP) is characterized by a granulomatous inflammation and may show various forms of clinical presentation, such as the acute, subacute, and chronic forms. The TH1-associated cytokines interleukin (IL) 12 and IL-18 and tumor necrosis factor alpha (TNF-alpha) may be involved in the pathogenesis of both the acute and chronic forms of HP. OBJECTIVE: To compare the release of IL-12, IL-18, and TNF-alpha from bronchoalveolar lavage (BAL) macrophages in these 2 forms of HP. METHODS: Patients underwent BAL 0 to 6 days after the last antigen exposure. Alveolar macrophages (AMs) from BAL in 6 patients with acute HP, 16 with chronic HP, and 11 controls were cultured for 24 hours. Cytokines in the culture supernatants were measured by enzyme-linked immunosorbent assay. RESULTS: The production of IL-12, IL-18, and TNF-alpha by AMs was increased in patients with both acute and chronic forms in either the absence or presence of lipopolysaccharide compared with controls. The levels of IL-12, IL-18, and TNF-alpha showed no difference between patients with acute and chronic HP. The spontaneous production of IL-12, IL-18, and TNF-alpha did not correlate with the CD4/CD8 ratio in BAL. The spontaneous and lipopolysaccharide-stimulated release of IL-12 showed a positive correlation with the percentage of lymphocytes (r = .470, P = .03; r = .496, P = .02; respectively) in BAL. CONCLUSIONS: This study demonstrates that an increased release of IL-12, IL-18, and TNF-alpha by AMs is associated with both the acute and chronic forms of HP.

104: Scandinavian journal of rheumatology, 2009 Feb 19, 102(2)
Interleukin-18 gene (IL18) promoter polymorphisms in patients with rheumatoid arthritis.

[Abstract]Objective: Rheumatoid arthritis (RA) is a complex autoimmune disease with a strong genetic contribution to its pathogenesis. Proinflammatory cytokines play an important role in the inflammatory process in RA patients. The synthesis of cytokines is genetically determined. Cytokine gene polymorphisms have been implicated in a number of diseases, including RA. Interleukin-18 (IL-18) is a proinflammatory cytokine involved in the pathogenesis of RA. There are, however, controversial reports that the IL18 promoter polymorphism may be an independent marker of RA susceptibility. The aim of the present study was to examine the IL18 promoter polymorphism in patients with RA in association with disease susceptibility and activity. Methods: We examined 404 patients with RA diagnosed according to the criteria of the American College of Rheumatology (ACR). Allele-specific polymerase chain reaction (PCR) and PCR restriction fragment length polymorphism (RFLP) methods were used to analyse the single-nucleotide polymorphisms (SNPs) rs1946518, rs187238, rs360718, rs360722, rs360721, rs549908, and rs5744292 in the promoter region of the IL18 gene. Results: There were no significant differences in the distributions of the genotypes and haplotypes between RA patients and a control group. Age at RA diagnosis was lower in carriers of the rs1946518 CC and rs187238 GG genotypes. Erosive disease was diagnosed more frequently in patients with the rs1946518 CC and AC genotypes than in AA homozygotes. Conclusion: These results show that these polymorphisms in the IL18 gene are associated only with some disease parameters and are generally not factors significantly influencing the course of RA.

105: Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2008 Dec, 59 Suppl 6
Increased levels of interleukin-12 and interleukin-18 in bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis.

[Abstract]We studied prospectively 43 patients with sarcoidosis and 13 normal subjects. IL-12 and IL-18 levels were measured using ELISA kits. Spirometry and body plethysmography were performed using an Elite DL Medgraphics body box. The sarcoidosis group was characterized by significantly higher median range of the plasma angiotensin-converting enzyme (ACE) concentration (72 vs. 34 U/l, P<0.0001), lymphocyte (34 vs. 14%, P<0.0001), CD4+ cells percentages (59 vs. 36%), and CD4/CD8 ratio (4.2 vs. 1.99, P<0.0001). The BALF IL-12 and IL-18 levels were significantly higher in sarcoidosis patients than in healthy subjects (4.1 pg/ml vs. 3.2 pg/ml; P<0.001 and 11.1 pg/ml vs. 6.15 pg/ml, P<0.0001, respectively). A negative correlation between BALF IL-12 and ACE plasma levels (r=-0.33, P<0.05) within the sarcoidosis group was found. Our data suggest a potential role of IL-12 and IL-18 in a local immunologic response in pulmonary sarcoidosis.

106: Molecular immunology, 2009 Nov, 47(1)
Increased atherosclerotic lesions and Th17 in interleukin-18 deficient apolipoprotein E-knockout mice fed high-fat diet.

[Abstract]Recent reports show T helper 17 (Th17) cells are involved in the pathogenesis of various chronic inflammatory diseases formerly categorized as Th1-mediated disorders. Interleukin-18 (IL-18) induces Th1 cells to produce interferon-gamma (IFN-gamma) which is proatherogenic, while cholesterol causes atherosclerosis and stimulates intact rat aortae to produce prostaglandin E(2) (PGE(2)), a strong regulator of IL-23 that expands Th17. We wanted to test whether Th17 is proatherogenic and whether cholesterol can induce the alternative Th17 pathway in IL-18 deficient apolipoprotein E-knockout (ApoE(-/-)) mice that have reduced Th1 cells, if they are fed high-cholesterol diet. IL-18(+/+)ApoE(-/-) and IL-18(-/-)ApoE(-/-) mice aged 5 weeks were fed high-cholesterol diet (HCD) and control littermates of IL-18(-/-)ApoE(-/-) low-cholesterol diet (LCD) for 12 weeks. At termination, cryosectioned aortic arches were stained for lesion measurement and immunohistochemistry. We found that serum cholesterol and triglyceride levels were significantly higher in IL-18(-/-)ApoE(-/-) mice on HCD and they also had significantly increased atherosclerosis compared with 18(+/+)ApoE(-/-) mice or IL-18(-/-)ApoE(-/-) mice on LCD. Increased atherosclerosis correlates with enhanced Th17-cells, IL-23-producing vascular smooth muscle cells (VSMC) and macrophages, and thin fibrous cap in lesions, the morphology indicative of unstable plaques prone to rupture. In vitro, cholesterol significantly enhances VSMCs explanted from IL-18(-/-)ApoE(-/-) but not IL-18(+/+)ApoE(-/-) aorta to produce IL-23 and homocysteine mediates secretion. This study suggests that in IL-18 deficiency, cholesterol in HCD synergize mechanistically with homocysteine to accelerate atherosclerosis via the alternative IL-23/Th17 pathway, demonstrating a new role for Th17 in atherosclerosis.

107: Shock (Augusta, Ga.), 2009 Nov, 32(5)
In vivo IL-18 supplementation ameliorates lethal acute lung injury in burn-primed endotoxemic mice: a novel anti-inflammatory role of IL-18.

[Abstract]Previously, we have found that a prior burn insult induces lethal acute lung injury (ALI) and overproduction of proinflammatory cytokines after LPS challenge in mice. The current study was aimed to determine the role of IL-18 in burn-induced LPS hypersensitivity. Except sham group, mice were subjected to a 15% total body surface area full-thickness burn and either untreated or treated with IL-18 alone, IL-18 + anti-IL-10 antibody or IL-18 + isotype immunoglobulin G. LPS was intravenously administered to all mice on the 11th day, and the mice were killed at the indicated time point, or survival was examined. We additionally examined cytokine production by splenic cells in vitro for the elucidation of immunologic mechanisms. Unexpectedly, the liver IL-18 decreased transiently after burn injury, and in vivo IL-18 supplementation improved survival and ameliorated ALI, as well as reducing the lung contents of all cytokines examined, except IL-10. Neutralization of IL-10 cancelled the protective effect of IL-18. In splenic macrophages obtained from burned mice, the production of macrophage inflammatory protein 2 (MIP-2), TNF-alpha, and IL-10 was augmented, whereas in vivo IL-18 supplementation decreased MIP-2 production, but increased IL-10 production. Furthermore, a physiological concentration of IL-18 directly attenuated MIP-2 production by splenic cells in vitro. Burn injury induces LPS hypersensitivity through augmented production of proinflammatory cytokines by systemic macrophages. IL-18 supplementation is protective for LPS-induced lethal ALI through the direct anti-inflammatory effect on macrophages as well as by in vivo acceleration of IL-10 production, and could thus be an effective prophylactic strategy against septic complications in critically ill patients.

108: Annals of the rheumatic diseases, 2010 Jan, 69(1)
The natural soluble form of IL-18 receptor {beta} exacerbates collagen-induced arthritis via modulation of T-cell immune responses.

[Abstract]OBJECTIVE: IL-18 is a pluripotent cytokine that has been implicated in the development of rheumatoid arthritis. A soluble form of the IL-18 receptor accessory protein (sIL-18Rbeta) with unknown function has recently been identified. This study examined the ability of sIL-18Rbeta to inhibit IL-18 biological activities and to modulate immune responses during collagen-induced arthritis (CIA). METHODS: Adenoviruses encoding sIL-18Rbeta were administered intravenously in type II collagen-immunised DBA/1 mice. Humoral responses were analysed by determining anti-bovine collagen type II (BCII) antibody levels by ELISA. Cytokine production by splenic T cells and cytokine levels in serum were measured by Luminex multi-analyte technology. CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) were measured by flow cytometry. RESULTS: Intravenous delivery of Ad5.sIL-18Rbeta in collagen-immunised mice led to enhanced transgene expression in splenic antigen-presenting cells (APC). A co-culture of these sIL-18Rbeta-transduced APC with purified splenic CD3(+) T cells led to a marked inhibition of IL-18-induced IFNgamma, IL-4 and IL-17 production by CD3(+) T cells. Remarkably, systemic treatment with Ad5.sIL-18Rbeta caused an exacerbation of arthritis, and histological evaluation of knee joints showed increased cartilage and bone erosion. No significant differences were observed in anti-BCII antibodies, but the aggravation was accompanied by decreased IFNgamma (-30%) and IL-4 (-44%) and increased IL-17 (+84%) production by splenic CD3(+) T cells. In addition, reduced circulating levels of CD4(+)CD25(+)Foxp3(+) Treg and anti-inflammatory IL-10 were shown. CONCLUSION: This study identifies sIL-18Rbeta as a novel IL-18 inhibitor, which promotes CIA after intravenous overexpression by affecting Treg levels and supporting a T helper type 17 response.

109: Fertility and sterility, 2010 Mar 1, 93(4)
Plasma interleukin-18 levels are increased in the polycystic ovary syndrome: relationship of carotid intima-media wall thickness and cardiovascular risk factors.

[Abstract]OBJECTIVE: To determine serum interleukin (IL)-18 levels and to find out whether IL-18 is associated with carotid intima-media wall thickness (IMT) and various cardiovascular risk factors in women with polycystic ovary syndrome (PCOS). DESIGN: A prospective, controlled study. SETTING: University hospital. PATIENT(S): Sixty women with PCOS and 60 healthy women were included this study. INTERVENTION(S): Serum levels IL-18, homocysteine (Hcy), C-reactive protein (CRP), IL-6, malonyldialdehyde (MDA), lipid and hormone profiles were measured. Carotid IMT was evaluated for both common carotid arteries. MAIN OUTCOME MEASURE(S): Serum IL-18, carotid IMT, Hcy, CRP, IL-6, MDA, and homeostasis model assessment of insulin resistance. RESULT(S): The evaluation, which was made without the obesity influence taken into consideration, revealed that patients with PCOS have increased serum IL-18 levels than that of the control group (214 +/- 102 vs. 170 +/- 78 pg/mL). The interaction between PCOS and obesity was seen to have statistical significance (F = 67.8). Body mass index (BMI), waist to-hip ratio, Hcy, and homeostasis model assessment of insulin resistance are independent determinants of plasma IL-18 in patients with PCOS. Elevated serum IL-18 levels were positively and significantly correlated with a greater carotid IMT. For Hcy and carotid IMT, the interaction between PCOS and obesity was found in a two-way ANOVA variation analysis (F = 48.5 and F = 81.5, respectively). CONCLUSION(S): Elevated serum IL-18 levels were associated with cardiovascular risk factors and carotid IMT in patients with PCOS.


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