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| Cytokine Database |
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CHEMOKINE (C-C MOTIF) LIGAND 20
LATEST LITERATURE
1: Clinical and experimental immunology, 2010 Sep 1, 299(3)
CCL20 is overexpressed in Mycobacterium tuberculosis-infected monocytes and inhibits the production of reactive oxygen species (ROS).
[Abstract]Summary CCL20 is a chemokine that attracts immature dendritic cells. We show that monocytes, cells characteristic of the innate immune response, infected with Mycobacterium tuberculosis express the CCL20 gene at a much higher level than the same cells infected with non-tuberculous mycobacteria. Interferon (IFN)-gamma, a fundamental cytokine in the immune response to tuberculosis, strongly inhibits both the transcription and the translation of CCL20. We have also confirmed that dendritic cells are a suitable host for mycobacteria proliferation, although CCL20 does not seem to influence their intracellular multiplication rate. The chemokine, however, down-regulates the characteristic production of reactive oxygen species (ROS) induced by M. tuberculosis in monocytes, which may affect the activity of the cells. Apoptosis mediated by the mycobacteria, possibly ROS-dependent, was also inhibited by CCL20.
2: American journal of physiology. Gastrointestinal and liver physiology, 2010 Jul 1,
Oxidative stress enhances IL-8 and inhibits CCL20 production from intestinal epithelial cells in response to bacterial flagellin.
[Abstract]Background: Intestinal epithelial cells act as innate immune sentinels, as the first cells that encounter diarrheal pathogens. They use pattern recognition molecules such as the Toll-like receptors (TLRs) to identify molecular signals found on microbes but not host cells or food components. TLRs cannot generally distinguish the molecular signals on pathogenic bacteria from those found in commensals, yet under healthy conditions epithelial immune responses are kept in check. We hypothesized that in the setting of tissue damage or stress, intestinal epithelial cells would upregulate their responses to TLR ligands to reflect the greater need for immediate protection against pathogens. Methods: We treated Caco-2 cells with the TLR5 agonist flagellin in the presence or absence of H(2)O(2) and measured chemokine production and intracellular signaling pathways. Results: H(2)O(2) increased flagellin-induced IL-8 (CXCL8) production in a dose-dependent manner. This was associated with synergistic phosphorylation of p38 MAP kinase and with prolonged I-kappaB degradation and NF-kappaB activation. The H2O2-mediated potentiation of IL-8 production required the activity of p38, tyrosine kinases, phospholipase Cgamma, and intracellular calcium, but not protein kinase C or protein kinase D. H(2)O(2) prolonged and augmented NF-kappaB activation by flagellin. In contrast to IL-8, CCL20 (MIP3alpha) production by flagellin was reduced by H(2)O(2), and this effect was not calcium-dependent. Conclusions: Oxidative stress biases intestinal epithelial responses to flagellin, leading to increased production of IL-8 and decreased production of CCL20. This suggests that epithelial cells are capable of sensing the extracellular environment and adjusting their antimicrobial responses accordingly.
3: Journal of translational medicine, 2010 May 10, 8(1)
CCL20/CCR6 expression profile in pancreatic cancer.
[Abstract]ABSTRACT: BACKGROUND: CCL20 and its receptor CCR6 have been shown to play a role in the onset, development and metastatic spread of various gastrointestinal malignancies. In this study, the expression profile and clinical significance of the CCL20/CCR6 system in distinct benign, pre-malignant and malignant pancreatic tissues was investigated. METHODS: Using RealTime-PCR, enzyme-linked immunosorbent assay (ELISA), Western Blot and immunohistochemistry, we have analyzed the expression profile of CCL20/CCR6 in resection specimens from patients with chronic pancreatitis (CP) (n = 22), pancreatic cystadenoma (PA) (n = 11) and pancreatic carcinoma (PCA) (n = 25) as well as in the respective matched normal pancreatic tissues. RESULTS: CCL20 mRNA and protein was weakly expressed in normal pancreatic tissues and CP and PA specimens but significantly up-regulated in PCA (8-fold) as compared to the matched normal tissue (P < 0.05). Moreover, CCL20 mRNA and protein expression was significantly associated with advanced T-category in patients with PCA (P < 0.05). CCR6 mRNA showed a significant up-regulation in all three disease entities as compared to normal tissues (P < 0.05, respectively). CONCLUSION: CCL20 and CCR6 were significantly up-regulated in PCA as compared to the normal pancreatic tissue and CCL20 was significantly associated with advanced T-category in PCA patients. This suggests that CCL20 and CCR6 play a role in the development and progression of PCA and may constitute potential targets for novel treatment strategies.
4: European journal of cancer (Oxford, England : 1990), 2010 Apr 30, 130(5)
ENO1, a potential prognostic head and neck cancer marker, promotes transformation partly via chemokine CCL20 induction.
[Abstract]The success of using glycolytic inhibitors for cancer treatment depends on studying the individual role of frequently deregulated glycolytic genes in cancer. This report aims to study the prognostic implication, and determine the cellular role and action mechanism of glycolytic ENO1 overexpression in head and neck cancer. The relationship of ENO1 mRNA expression in 44-pair clinical specimens with patient clinicopathologic characteristics was analysed by semi-quantitative RT-PCR, Kaplan-Meier survival curve and Cox model analyses. Following ectopic ENO1 expression or knockdown, we studied the proliferative, migratory, invasive, colony-forming and tumourigenic abilities of ENO1-genetically altered cells. DNA microarray analysis was used to identify downstream targets responsible for the ENO1 action in the cells. The expression of ENO1 mRNA was increased in 68% of tumour (T) specimens when compared to their normal (N) counterparts, and positively associated with clinical progression (p<0.05). High ENO1 expression (T/N2) was frequently observed in the patients with large primary tumours, late clinical stages or advanced neck metastasis. Moreover, high ENO1 patients had significantly poorer clinical outcomes than low expressers (T/N<2). Ectopic ENO1 expression stimulated cell transformation, invasion and tongue tumour formation. ENO1 knockdown abrogated the stimulation. Suppression of ENO1-induced proinflammatory CCL20 chemokine expression significantly attenuated its stimulatory effects on cell transformation and invasion. A concordant expression of ENO1 and CCL20 was validated both in ENO1-expresing cells and in clinical specimens. Together, we demonstrate a prognostic role of ENO1 overexpression in head and neck cancer and ENO1-mediated promotion of cell transformation and invasion partly via induced CCL20 expression.
5: Cytokine, 2010 Apr 16, 130(5)
OX40 induces CCL20 expression in the context of antigen stimulation: An expanding role of co-stimulatory molecules in chemotaxis.
[Abstract]OX40 is an inducible co-stimulatory molecule expressed by activated T cells. It plays an important role in the activation and proliferation of T lymphocytes. Recently, some co-stimulatory molecules have been shown to direct leukocyte trafficking. Chemotaxis is essential for achieving an effective immune response. CCL20 is an important chemoattractant produced by activated T cells. In this study, using DO11.10 mice whose transgenic T cell receptor specifically recognizes ovalbumin, we demonstrate that ovalbumin induces OX40 expression in CD4+ lymphocytes. Further stimulation of OX40 by OX40 activating antibody up-regulates CCL20 production. Both NF-kappaB dependent and independent signaling pathways are implicated in the induction of CCL20 by OX40. Finally, we primed the DO11.10 splenocytes with or without OX40 activating antibody in the presence of ovalbumin. Intranasal administration of the cell lysates derived from the cells with OX40 stimulation results in more severe leukocyte infiltration in the lung of DO11.10 mice, which is substantially attenuated by CCL20 blocking antibody. Taken together, this study has shown that activation of OX40 induces CCL20 expression in the presence of antigen stimulation. Thus, our results broaden the role of OX40 in chemotaxis, and reveal a novel effect of co-stimulatory molecules in orchestrating both T cell up-regulation and migration.
6: European journal of immunology, 2010 Jan 25,
CCL20/CCR6 Blockade Enhances Immunity to Respiratory Syncytial Virus by Impairing Recruitment of Dendritic Cells.
[Abstract]Chemokines are important mediators of the immune response to pathogens, but can also promote chronic inflammatory states. Chemokine receptor 6 (CCR6) is found on immature dendritic cells and effector/memory T cells, and binds a single ligand, CCL20, with high affinity. Here we investigated the role of CCL20 and CCR6 in a pulmonary viral infection caused by respiratory syncytial virus (RSV), a ubiquitous virus that can cause severe pulmonary complications. Neutralization of CCL20 during RSV infection significantly reduced lung pathology and favored a Th1 effector response. CCR6-deficient animals recapitulated this phenotype, and additionally showed enhanced viral clearance when compared to WT mice. No differences were observed in migration of T cells to the lungs of CCR6-/- animals, however, a significant reduction was observed in numbers of conventional DC (cDC), but not plasmacytoid DC, in CCR6-/- mice. A pathogenic phenotype could be reconstituted in CCR6-/- mice by supplying cDC into the airway, indicating that mere number of cDC dictates the adverse response. Our data suggest that blockade of the CCL20/CCR6 pathway provides an environment whereby the attenuated recruitment of cDC alters the balance of innate immune cells and mediates the efficient antiviral response to RSV.
7: Immunological investigations, 2010, 39(1)
Higher Levels of CCL20 Expression on Peripheral Blood Mononuclear Cells of Chinese Patients with Inflammatory Bowel Disease.
[Abstract]This study aimed at characterizing the levels of CCL20 mRNA transcripts in peripheral mononuclear blood cells (PMBC) of 56 Chinese patients with inflammatory bowel disease (IBD), 30 other intestinal diseases and 30 healthy controls by quantitative real time polymerase chain reaction. The levels of CCL20 mRNA transcripts in PBMC of patients with IBD were significantly higher than that of patients with non-IBD intestinal diseases and healthy controls (p < 0.01) and the CCL20 expression in active IBD patients was significantly higher than that in remission patients (p < 0.01). Importantly, the levels of CCL20 expression in PBMC were significantly correlated with the degrees of disease severity, the levels of erythrocyte sedimentation rate and C-reaction protein, but not hemoglobin, in patients with IBD (p < 0.01). Furthermore, the levels of CCL20 expression in active IBD patients after treatment with salazosulphapyridine or prednisone were significantly reduced, as compared with before treatment (p < 0.01). Therefore, analysis of CCL20 expression in PBMC may be used as a surrogate measure for evaluation of IBD activity, disease progression and therapeutic efficacy in Chinese IBD patients.
8: The Journal of investigative dermatology, 2010 Jan 7,
Regulation of the Psoriatic Chemokine CCL20 by E3 Ligases Trim32 and Piasy in Keratinocytes.
[Abstract]Psoriasis is an inflammatory skin disorder with aberrant regulation of keratinocytes and immunocytes. Although it is well known that uncontrolled keratinocyte proliferation is largely driven by proinflammatory cytokines from the immunocytes, the functional role of keratinocytes in the regulation of immunocytes is poorly understood. Recently, we found that tripartite motif-containing protein 32 (Trim32), an E3-ubiquitin ligase, is elevated in the epidermal lesions of human psoriasis. We previously showed that Trim32 binds to the protein inhibitor of activated STAT-Y (Piasy) and mediates its degradation through ubiquitination. Interestingly, the Piasy gene is localized in the PSORS6 susceptibility locus on chromosome 19p13, and Piasy negatively regulates the activities of several transcription factors, including NF-kappaB, STAT, and SMADs, that are implicated in the pathogenesis of psoriasis. In this study, we show that Trim32 activates, and Piasy inhibits, keratinocyte production of CC chemokine ligand 20 (CCL20), a psoriatic chemokine essential for recruitment of DCs and T helper (Th)17 cells to the skin. Further, Trim32/Piasy regulation of CCL20 is mediated through Piasy interaction with the RelA/p65 subunit of NF-kappaB. As CCL20 is activated by Th17 cytokines, the upregulation of CCL20 production by Trim32 provides a positive feedback loop of CCL20 and Th17 activation in the self-perpetuating cycle of psoriasis.Journal of Investigative Dermatology advance online publication, 7 January 2010; doi:10.1038/jid.2009.416.
9: Oncology reports, 2009 Dec, 22(6)
Adipocyte culture medium stimulates invasiveness of MDA-MB-231 cell via CCL20 production.
[Abstract]We explored whether adipocyte culture medium affects the secreted chemokine profile of tumor cells, because adipocytes stimulate progression or metastasis of breast cancer cells, and chemokines secreted from tumor cells are involved in these processes. CCL20 expression was dramatically increased, and an NF-kappaB blocker completely inhibited adipocyte culture medium-induced CCL20 expression in MDA-MB-231 cells. We showed that adipocyte culture medium increased the production of TNF-alpha in MDA-MB-231 cells, which stimulated CCL20 expression in an autocrine fashion. Our data also showed that CCL20 increased the migration and invasiveness of MDA-MB-231 cells, but did not affect the proliferation of these cells.
10: Molecular immunology, 2009 Oct 20,
Cloning, expression and functional characterization of chicken CCR6 and its ligand CCL20.
[Abstract]Chemokines are key molecules that drive migration of lymphoid and myeloid cells toward organs in basal as well as inflammatory conditions. By recruiting immature dendritic cells to the mucosal surfaces, CCL20 acts in the very early events leading to the development of a specific immune response. In order to characterize dendritic cells in birds and better understand their role in the initiation of immune responses against pathogens of economic as well as human health relevance, we have cloned and expressed chicken CCL20 (chCCL20) and its specific receptor chCCR6. chCCL20 has 51% identity (60% similarity) with human CCL20, while the chicken receptor and its human counterpart display nearly 55% identity (and up to 70% similarity). chCCL20 and its specific receptor chCCR6 mRNAs are mainly expressed in bone marrow, secondary lymphoid organs and in the mucosal surfaces, in particular lungs and intestine. Both receptor and chemokine are functionally active when expressed as genuine or tagged proteins in mammalian expression systems, that is chCCR6 is mainly located at the cell surface within lipid rafts like its human counterpart. And secondly, both human and chicken chemokines were able to drive the migration of either chicken or human CCR6-transfected cells.
11: The Journal of rheumatology, 2009 Oct 1, 221(1)
Proinflammatory Cytokines Synergistically Enhance the Production of Chemokine Ligand 20 (CCL20) from Rheumatoid Fibroblast-like Synovial Cells in vitro and Serum CCL20 Is Reduced in vivo by Biologic Disease-modifying Antirheumatic Drugs.
[Abstract]OBJECTIVE: Chemokine ligand 20 (CCL20) is a selective ligand for chemokine receptor 6 (CCR6). We investigated, both in vitro and in vivo, whether CCL20 is critically involved in the disease process of rheumatoid arthritis (RA). METHODS: In vitro study investigated the effect of proinflammatory cytokines and biologic disease-modifying antirheumatic drugs (DMARD) on the production of CCL20 by rheumatoid fibroblast-like synovial cells (FLS). The in vivo role of CCL20 was studied by screening for serum CCL20 concentration in patients with RA during the therapeutic course of biologic DMARD, i.e., infliximab, etanercept, and tocilizumab. RESULTS: Spontaneous CCL20 production from rheumatoid FLS was minimal; however, its production was significantly stimulated by interleukin 1ss (IL-1ss), tumor necrosis factor-alpha (TNF-alpha), or IL-17. IL-1ss was the most potent for stimulating the production of CCL20. CCL20 production was synergistically augmented by a combination of IL-1ss, TNF-alpha, and IL-17. In contrast, interferon-gamma suppressed IL-1ss-induced CCL20 production. IL-6, in combination with soluble IL-6 receptor (sIL-6R), did not modulate CCL20 production, whereas IL-1ss-induced, TNF-alpha-induced, and IL-17-induced production were increased by IL-6. These production levels were clearly suppressed by biologic DMARD in vitro. Serum CCL20 was significantly higher in RA than in control subjects, and was clearly decreased by the treatment with infliximab, etanercept, and tocilizumab. CONCLUSION: Proinflammatory cytokines modulate the production of CCL20 from FLS. Our data suggest that therapeutic efficacy of biologic DMARD may result from the inhibition of CCL20 production in rheumatoid synovium.
12: Innate immunity, 2009 Aug 26, 129(9)
PLC, p38/MAPK, and NF{kappa} B-mediated induction of MIP-3{alpha}/CCL20 by porphyromonas gingivalis.
[Abstract]Macrophage inflammatory protein-3alpha/C-C chemokine ligand 20 (MIP-3alpha/CCL20) is an antimicrobial peptide that plays an important role in innate immunity. In addition to direct microbicidal effects, MIP-3alpha/CCL20 also exhibits cytokine-like functions that are critical during dendritic cell activation. The aim of the present study was to investigate further which signaling pathways are involved in the MIP-3alpha/CCL20 mRNA expression in response to whole-cell Porphyromonas gingivalis. Primary gingival epithelial cells (GECs) and the immortalized oral keratinocyte cell-line OKF6/TERT-2 were stimulated with whole-cell P. gingivalis. Prior to stimulation, GECs and OKF6/TERT-2 cells were pretreated with specific inhibitors for nuclear-factor-kappaB (NF-kappaB), mitogen-activated protein kinase (MAPK), phospholipase C (PLC), and phosphatidylinositol-3-kinase (PI3K). In GECs and OKF6/TERT-2 cells, activation of NF-kappaB was examined after exposure to P. gingivalis. The gene expression of MIP-3alpha/CCL20 was significantly induced in response to P. gingivalis (P 13: Arteriosclerosis, thrombosis, and vascular biology, 2009 Oct, 29(10)
Interplay between human adipocytes and T lymphocytes in obesity: CCL20 as an adipochemokine and T lymphocytes as lipogenic modulators.
[Abstract]OBJECTIVE: Adipose tissue (AT) plays a major role in the low-grade inflammatory state associated with obesity. The aim of the present study was to characterize the human AT lymphocytes (ATLs) and to analyze their interactions with adipocytes. METHODS AND RESULTS: Human ATL subsets were characterized by flow cytometry in subcutaneous ATs from 92 individuals with body mass index (BMI) ranging from 19 to 43 kg/m(2) and in paired biopsies of subcutaneous and visceral AT from 45 class II/III obese patients. CD3(+) ATLs were composed of effector and memory CD4(+) helper and CD8(+) cytotoxic T cells. The number of ATLs correlated positively with BMI and was higher in visceral than subcutaneous AT. Mature adipocytes stimulated the migration of ATLs and released the chemokine CCL20, the receptor of which (CCR6) was expressed in ATLs. The expression of adipocyte CCL20 was positively correlated with BMI and increased in visceral compared to subcutaneous adipocytes. ATLs expressed inflammatory markers and released interferon gamma (IFN gamma). Progenitor and adipocyte treatment with ATL-conditioned media reduced the insulin-mediated upregulation of lipogenic enzymes, an effect involving IFN gamma. CONCLUSIONS: Therefore, crosstalk occurs between adipocytes and lymphocytes within human AT involving T cell chemoattraction by adipocytes and modulation of lipogenesis by ATLs.
14: Zhonghua wai ke za zhi [Chinese journal of surgery], 2009 Apr 15, 47(8)
[Clone screening and interference efficiency of seed cells with CCL20 gene knockdown for tissue-engineered skin]
[Abstract]OBJECTIVE: To screen stable cell clones of CCL20 gene knockdown and assess their interference effects, recombinant lentivirus vectors with CCL20 gene specific shRNA were applied to infect human immortal keratinocyte line (HaCaT). METHODS: The three pHSER-CCL20-shRNA-GFP vectors (pHCG-1 and pHCG-2 were CCL20 gene specific, and pHCG-3 was used as mismatch control) have been previously constructed. The virus packaging cell line 293FT was transfected with these vectors by using CaCl2 methods to produce lectiviral particles. After the viral titers of these three harvested cell supernatants were determined by flow cytometry, HaCaT cells were transfected by these viruses and screened under the pressure of G418. The CCL20 mRNA from HaCaT cell clones and the CCL20 protein levels in the supernatants of HaCaT cell clones were detected by Real-time RT-PCR and ELISA, respectively. RESULTS: The titers of three lentiviruses were 7.08 x 10(5) transduced units (TU)/ml, 1.88 x 10(5) TU /ml and 2.08 x 10(5) TU/ml, respectively. Two HaCaT cell clones from each lectiviral vectors were obtained after G418 screening for 5 - 8 weeks. Four CCL20 gene specific clones showed stable interference effect in both Real-time RT-PCR and ELISA. The mRNA expression and protein level of CCL20 gene specific clones were down regulated significantly. CONCLUSIONS: The four human immortal keratinocyte clones with long term CCL20 gene knockdown have been screened by recombinant lentivirus vectors with CCL20 gene specific shRNA. These clones might be served as seed cells for novel tissue-engineered skin with lower rejection.
15: Innate immunity, 2009 Jun 30, 48(7)
Modulation of Expression of Innate Immunity Markers CXCL5/ENA-78 and CCL20/MIP3{alpha} by Protease Activated Receptors (PARs) in Human Gingival Epithelial Cells.
[Abstract]Protease-activated receptors (PARs) are G-protein-coupled receptors with an active role in host defense. The two most highly expressed members of the PAR family in gingival epithelial cells (GECs) are PAR1 and PAR2. The major virulence factors of periodontal pathogen Porphyromonas gingivalis are its proteases which can activate PAR2. However, little is known about the function of PARs in GECs when they are activated by their endogenous agonist enzymes. The purpose of this study was to characterize how the expression of innate immune markers is modulated when PAR1 and PAR2 are activated by their agonist enzymes, thrombin and trypsin, respectively. Here, we report that activation of PAR1 and PAR2 induces cell proliferation at low concentration. Activation of PAR via proteolytic activity of thrombin and trypsin induces expression of CXCL5/ENA-78 and CCL20/MIP3alpha in a concentration-dependent manner. Induction of CXCL5 via PAR1 was inhibited in the presence of PAR1 cleavage blocking antibodies and by PAR1 siRNA. The induction of CXCL5 and CCL20 via PAR2 was inhibited by PAR2 siRNA. These findings indicate an active role in innate immune responses by PAR1 and PAR2 in GECs. Modulation of innate immunity by PARs may contribute to co-ordinated and balanced immunosurveillance in GECs.
16: Cytokine, 2009 Aug, 47(2)
CCL20 produced in the cytokine network of rheumatoid arthritis recruits CCR6+ mononuclear cells and enhances the production of IL-6.
[Abstract]Although a notable amount of CCL20 is detectable in the synovial fluid of human rheumatoid arthritis (RA), its role in the pathogenesis of RA remains to be determined. IL-1beta vigorously induced the production of CCL20 from FLSs of human RA and the production of CCL20 induced by TNF-alpha was partially attributed to a trace amount of IL-1beta induced by TNF-alpha. Although IL-6 failed to induce CCL20, TNF-alpha-induced IL-6 enhanced the production of CCL20 in an autocrine/paracrine manner. To determine the role of CCL20 and its sole receptor CCR6 in the recruitment of mononuclear cells (MNCs) into the inflamed joint of RA, conditioned medium of IL-1beta-stimulated FLSs was used in migration assays. The conditioned medium significantly recruited CCR6(+) MNCs in a CCL20-dependent manner. The production of CCL20 induced by TNF-alpha and IL-1beta was modified by helper-T-cell-derived cytokines. Interestingly, CCL20 enhanced the production of IL-6 coordinately with the stimulation of IL-17 but not with that of IFN-gamma. These findings imply FLSs stimulated by proinflammatory cytokines recruit CCR6(+) MNCs including IL-17-producing-helper T cells into the inflamed joint, leading to the enhancement of the production of CCL20, which chemokine and IL-17 coordinately induce proinflammatory cytokines.
17: American journal of reproductive immunology (New York, N.Y. : 1989), 2009 Jul, 62(1)
CCL20/MIP3alpha is a novel anti-HIV-1 molecule of the human female reproductive tract.
[Abstract]PROBLEM: CCL20/MIP3alpha is a chemokine for immature dendritic cells as well as an antibacterial against gram-positive and gram-negative bacteria. The role of CCL20/MIP3alpha as an antiviral is unknown. In this study, we have examined the production of CCL20/MIP3alpha by epithelial cells from the upper female reproductive tract as well as its activity as an antiviral molecule. METHOD OF STUDY: Primary uterine and Fallopian tube epithelial cells were treated with Poly(I:C) and CCL20/MIP3alpha mRNA and protein was measured by Realtime RT-PCR and ELISA assays. Anti-HIV activity was determined using an indicator cell line TZM-bl and quantified by using a luminometer. RESULTS: Primary uterine and Fallopian tube epithelial cells produce CCL20/MIP3alpha constitutively and the production is enhanced following stimulation with viral double-stranded RNA mimic Poly(I:C). Recombinant CCL20/MIP3alpha was able to inhibit both T-cell-tropic X4/IIIB and macrophage-tropic R5/BaL HIV-1 when virus was directly incubated with CCL20/MIP3alpha but not when CCL20/MIP3alpha was added to cells either prior to infection or post-infection. This suggests that the mechanism of inhibition is likely to be a direct interaction between HIV-1 and CCL20/MIP3alpha. CONCLUSION: This study demonstrates that CCL20/MIP3alpha is an important endogenous anti-HIV-1 microbicide of the female reproductive tract.
18: Journal of cellular physiology, 2009 Oct, 221(1)
CCL20/CCR6 chemokine/receptor expression in bone tissue from osteoarthritis and rheumatoid arthritis patients: different response of osteoblasts in the two groups.
[Abstract]Subchondral bone remodeling in osteoarthritis (OA) and rheumatoid arthritis (RA) is mainly characterized by the formation of osteophytes/fibrosis and by the presence of infiltrating cells associated to bone resorption. In this study we analyzed CC (cysteine cysteine motif) chemokine ligand (CCL)20 and CC chemokine receptor (CCR)6 function in subchondral bone tissue and osteoblasts isolated from OA and RA patients. CCL20/CCR6 expression was evaluated by immunohistochemical techniques in bone tissue from OA and RA patients. CCL20-functional tests were performed on osteoblasts isolated from OA and RA patients to evaluate enzymatic response and cell proliferation. Moreover, we assessed Akt phosphorylation as the major signaling pathway for CCL20. In bone tissue biopsies we found that osteoblasts from both OA and RA patients expressed CCR6 while CCL20 was expressed only by RA osteoblasts. Both CCR6 and CCL20 were highly expressed in osteocytes and mononuclear cells from only RA patients. CCL20-stimulated OA osteoblasts showed a significant increase in beta-N-acetylhexosaminidase release compared to RA. Conversely, a significant increase in cellular proliferation was found only in CCL20-stimulated RA osteoblasts associated to Akt phosphorylation. These data were confirmed in bone tissue biopsies. This study demonstrates a different expression of CCL20-positive osteoblasts in OA versus RA disease that seem to be associated with the presence of infiltrating mononuclear cells. Moreover, CCL20 stimulation resulted in a greater proliferative response in RA osteoblasts compared to OA osteoblasts, mediated by Akt signaling, while OA osteoblasts showed increased enzymatic activity, thus suggesting a differential role of this chemokine in OA and RA.
19: International journal of cancer. Journal international du cancer, 2009 Aug 15, 125(4)
The chemokine CCL20 and its receptor CCR6 in human malignancy with focus on colorectal cancer.
[Abstract]Chemokines are a superfamily of small chemotactic cytokines, which interact with their G-protein-coupled receptors. These interactions regulate multiple physiological functions, particularly tissue architecture and compartment-specific migration of white blood cells. It has been found that the chemokine/chemokine receptor system has been utilized by cancer cells for migration and metastasis. The chemokine receptor CCR6 is expressed in colorectal cancer and several other cancer types, and stimulation by its physiological chemokine ligand CCL20 has been reported to promote cancer cell proliferation and migration in vitro. Moreover, CCR6/CCL20 interactions apparently play a role in organ selective liver metastasis of colorectal cancer. Here, we review the literature on expression patterns of CCL20 and CCR6 and their physiological interactions as well as the currently presumed role of CCR6 and CCL20 in the formation of colorectal cancer liver metastasis, providing a potential basis for novel treatment strategies.
20: Journal of clinical immunology, 2009 Sep, 29(5)
Chlamydophila pneumoniae triggers release of CCL20 and vascular endothelial growth factor from human bronchial epithelial cells through enhanced intracellular oxidative stress and MAPK activation.
[Abstract]BACKGROUND: Chlamydophila pneumoniae may contribute to the pathogenesis of asthmatic airway inflammation through chemical mediators secreted by C. pneumoniae-infected bronchial epithelial cells (BECs). Recently, CCL20 and vascular endothelial growth factor (VEGF) were reported to be released from BECs and to play a role in the pathogenesis of asthma. OBJECTIVE AND METHODS: To determine if C. pneumoniae infection of BECs induces the secretion of CCL20 and VEGF, we measured that by ELISA in human BECs infected with C. pneumoniae. Transcripts of CCL20 and VEGF were assayed by semi-quantitative RT-PCR. To investigate the underlying mechanism, the activation of MAPK and intracellular reactive oxygen species (ROS) in these C. pneumoniae-infected BECs was measured, as well as the effects of inhibitors of MAPK and ROS on CCL20 and VEGF expression. RESULTS: Compared with non-infected BECs, C. pneumoniae-infected BECs showed enhanced secretion of CCL20 and VEGF. C. pneumoniae-infected BECs also showed enhanced intracellular ROS and an increased ratio of phosphorylated to non-phosphorylated p38. Inhibition of p38 suppressed CCL20 and VEGF secretion, as did a NADPH oxidase blocker and an antioxidant, in C. pneumoniae-infected BECs. CONCLUSION: C. pneumoniae infection of BECs may play a role in the pathogenesis of asthma through the enhanced production of CCL20 and VEGF. The association between increased cytokine production and increased intracellular ROS suggests that antioxidants may benefit asthmatics in selected situations.
21: Rheumatology (Oxford, England), 2009 Jul, 48(7)
Serum amyloid A protein stimulates CCL20 production in rheumatoid synoviocytes.
[Abstract]OBJECTIVE: Although serum amyloid A (SAA) has been used as a marker of inflammation, its role in leucocyte recruitment and angiogenesis has not been well established in RA. CCL20 is a chemokine involved in the migration of CCR6-expressing Th17 cells. To study the contribution of SAA to the recruitment of Th17 cells, we investigated the effects of SAA on CCL20 production by RA synoviotytes. METHODS: Synoviocytes isolated from RA patients were stimulated with recombinant SAA and cellular supernatants were analysed by CCL20-specific ELISA. CCL-20 mRNA expression was analysed by RT-PCR. RESULTS: SAA is a most potent inducer of CCL20 secretion in RA synoviocytes compared with other inflammatory cytokines (IL-1beta, TNF-alpha and IL-17A). SAA stimulation induced CCL20 mRNA expression in RA synoviocytes, which was not affected by polymyxin B pre-treatment. SAA-induced CCL20 production was down-regulated by NF-kappaB inhibition and partially by c-jun N-terminal kinase (JNK) inhibition. SAA-induced CCL20 production was also suppressed by dexamethasone or FK506. CONCLUSION: These findings suggest that SAA may be implicated in the recruitment of lymphocytes, including CCR6-expressing Th17 cells, in RA synovium by up-regulating CCL20 production in synoviocytes.
22: European journal of immunology, 2009 Apr, 39(4)
Prolactin enhances basal and IL-17-induced CCL20 production by human keratinocytes.
[Abstract]Psoriasis vulgaris is an autoimmune dermatosis with Th17 infiltration. Prolactin (PRL) may participate in the pathogenesis of psoriasis. The chemokine CCL20 recruits Th17 cells, and CCL20 production by epidermal keratinocytes is enhanced in psoriatic lesions. We examined the in vitro effects of PRL on CCL20 production in human keratinocytes. PRL increased basal and IL-17-induced CCL20 secretion, and mRNA expression in keratinocytes. CCL20 production by PRL was suppressed by antisense oligonucleotides against the AP-1 components c-Fos and c-Jun, whereas that by IL-17 was suppressed by antisense NF-kappaB p50 and p65. CCL20 production induced by PRL plus IL-17 was suppressed by antisense c-Fos, c-Jun, p50, and p65. PRL alone increased the transcriptional activity of AP-1, and c-Fos and c-Jun expression; moderately enhanced NF-kappaB activity and IkappaBalpha phosphorylation; and potently increased IL-17-induced NF-kappaB activity. MEK and JNK inhibitors suppressed PRL- or PRL-plus-IL-17-induced CCL20 production and AP-1 activities. MEK inhibitor suppressed PRL-induced c-Fos expression, whereas JNK inhibitor suppressed c-Jun expression. PRL induced ERK and JNK phosphorylation. These results suggest that PRL may enhance basal and IL-17-induced CCL20 production in keratinocytes by AP-1 and NF-kappaB activation, which is partially mediated via MEK/ERK and JNK. PRL may promote Th17 infiltration into psoriatic lesions via CCL20.
23: International immunopharmacology, 2009 Jul, 9(7-8)
Fusion of antigen to chemokine CCL20 or CXCL13 strategy to enhance DNA vaccine potency.
[Abstract]DNA vaccination is a promising method to induce specific immune responses. However, it remains challenging to enhance DNA vaccine potency. Chemokines were used as adjuvants to improve the efficacy of DNA vaccination. Herein, we fused murine chemokine CCL20 or CXCL13 to a model antigen green fluorescent protein (GFP). The fusion DNA vaccines enhanced specific anti-GFP immune responses in mice compared with vector pEGFP-N1. Co-immunization with both of chemokine-GFP fusion constructs induced the significantly highest level of humoral immune responses. CCL20-GFP or CXCL13-GFP fusion DNA vaccine induced predominant IgG2a or IgG1 response respectively. However, co-immunization with both of these fusion DNA vaccines induced a predominant IgG2a response. Therefore, fusing chemokine CXCL13 or CCL20 to antigen provides new attractive strategy to enhance the immunogenicity of DNA vaccine and modulate immune responses.
24: Blood, 2009 May 28, 113(22)
Induction of CCL20 production by Kaposi sarcoma-associated herpesvirus: role of viral FLICE inhibitory protein K13-induced NF-kappaB activation.
[Abstract]Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent of Kaposi sarcoma (KS), an angioproliferative lesion characterized by dramatic angiogenesis and inflammatory infiltration. In this study, we report that expression of chemokine CCL20, a potent chemoattractant of dendritic cells and lymphocytes, is strongly induced in cultured cells either by KSHV infection or on ectopic expression of viral FLICE inhibitory protein K13. This induction is caused by transcriptional activation of CCL20 gene, which is mediated by binding of the p65, p50, and c-Rel subunits of the transcription factor nuclear factor-kappaB (NF-kappaB) to an atypical NF-kappaB-binding site present in the CCL20 gene promoter. The CCL20 gene induction is defective in K13 mutants that lack NF-kappaB activity, and can be blocked by specific genetic and pharmacologic inhibitors of the NF-kappaB pathway. CCR6, the specific receptor for CCL20, is also induced in cultured cells either by KSHV infection or on K13 expression. Finally, expression of CCL20 and CCR6 is increased in clinical samples of KS. These results suggest that KSHV and K13-mediated induction of CCL20 and CCR6 may contribute to the recruitment of dendritic cells and lymphocytes into the KS lesions, and to tumor growth and metastases.
25: Biochimica et biophysica acta, 2009 May, 1789(5)
Toll-like receptor 5- and lymphotoxin beta receptor-dependent epithelial Ccl20 expression involves the same NF-kappaB binding site but distinct NF-kappaB pathways and dynamics.
[Abstract]Canonical and alternative NF-kappaB pathways depend on distinct NF-kappaB members and regulate expression of different gene subset in inflammatory and steady state conditions, respectively. In intestinal epithelial cells, both pathways control the transcription of the gene coding the CCL20 chemokine. Lymphotoxin beta receptor (LTbetaR) mediates long lasting CCL20 expression whereas Toll-like receptor 5 (TLR5) signals promote inducible and transient activation. Here, we investigated whether the regulation of ccl20 expression involves different promoter sites and NF-kappaB molecules in response to TLR5 and LTbetaR stimulation. In epithelial cells, both stimulation required the same promoter regions, especially the NF-kappaB binding site but involved different NF-kappaB isoforms: p65/p50 and p52/RelB, for TLR5 and LTbetaR-dependent activation, respectively. The dynamic of activation and interaction with CCL20-specific NF-kappaB site correlated with gene transcription. Similar Ccl20 expression and NF-kappaB activation was found in the small intestine of mice stimulated with TLR5 and LTbetaR agonists. In summary, different NF-kappaB pathways modulate CCL20 transcription by operating on the same NF-kappaB binding site in the same cell type.
26: The Journal of investigative dermatology, 2009 Sep, 129(9)
Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis.
[Abstract]T helper (Th) 17 cells have recently been implicated in psoriasis pathogenesis, but mechanisms of how these cells traffic into inflamed skin are unknown. By immunostaining for interleukin (IL)-17A and IL-22, we show numerous cells present in psoriasis lesions that produce these cytokines. We next found that Th17 cytokines (IL-17A, IL-22, and tumor necrosis factor (TNF)-alpha) markedly increased the expression of CC chemokine ligand (CCL) 20, a CC chemokine receptor (CCR)6 ligand, in human keratinocyte monolayer and raft cultures in a dose- and time-dependent manner. Lastly, we showed in mice that subcutaneous injection with recombinant IL-17A, IL-22, or TNF-alpha led to the upregulation of both CCL20 and CCR6 expression in skin as well as cutaneous T-cell infiltration. Taken together, these data show that Th17 cytokines stimulate CCL20 production in vitro and in vivo, and thus provide a potential explanation of how CCR6-positive Th17 cells maintain their continual presence in psoriasis through a positive chemotactic feedback loop.
27: The Journal of biological chemistry, 2009 Feb 20,
CCR6 regulation of the actin cytoskeleton orchestrates human beta defensin-2 and CCL20-mediated restitution of colonic epithelial cells.
[Abstract]Intestinal inflammation is exacerbated by defects in the epithelial barrier and subsequent infiltration of microbes and toxins into the underlying mucosa. Production of chemokines and antimicrobial peptides by an intact epithelium provide the first line of defense against invading organisms. In addition to its antimicrobial actions, human beta defensin-2 (HBD2) may also stimulate the migration of dendritic cells through binding the chemokine receptor CCR6. As human colonic epithelium expresses CCR6, we investigated the potential of HBD2 to stimulate intestinal epithelial migration. HBD2 was equipotent to CCL20 in stimulating migration of polarized human intestinal Caco2 and T84 cells and non-transformed IEC6 cells. Neutralizing antibodies confirmed HBD2 and CCL20 engagement to CCR6 were sufficient to induce epithelial cell migration. Consistent with restitution, motogenic concentrations of HBD2 and CCL20 did not induce proliferation. Stimulation with those CCR6 ligands leads to calcium mobilization and elevated active RhoA, phosphorylated myosin light chain and F-actin accumulation. HBD2 and CCL20 were unable to stimulate migration in the presence of either Rho-kinase or PI3K inhibitors or an intracellular calcium chelator. Together, these data indicate that the canonical wound healing regulatory pathway, along with calcium mobilization regulate CCR6-directed epithelial cell migration. These findings expand the mechanistic role for chemokines and HBD2 in mucosal inflammation to include immunocyte trafficking and killing of microbes with the concomitant activation of restitutive migration and barrier repair.
28: Investigational new drugs, 2009 Feb 10,
Trastuzumab-induced CCL20 and interleukin-8 mRNA in human whole blood ex vivo.
[Abstract]Heparinized human whole blood from 16 adult volunteers was stimulated with achievable blood concentrations of trastuzumab and rituximab at 37 degrees C for 4 h, then CCL20, IL8, and beta-actin mRNA were quantified. The fold increase of beta-actin was all less than 1.5, and heat aggregated IgG induced both IL8 and CCL20 mRNA in all cases, suggesting that the assay was performed appropriately. Rituximab reduced the levels of CCL20 mRNA in approximately 1/3 of subjects, whereas 50 mug/ml trastuzumab induced IL8 and CCL20 mRNA in more than half of subjects. Although the results do not directly indicate the toxicity of antibody medicines, the individual variation found under physiological ex vivo condition will be an interesting clinical research model for drug safety analysis.
29: Clinical immunology (Orlando, Fla.), 2009 Mar, 130(3)
Enhanced expression of CCL20 in human Helicobacter pylori-associated gastritis.
[Abstract]CC chemokine ligand 20 (CCL20) attracts CC chemokine receptor 6 (CCR6)-expressing cells. Using endoscopic biopsies taken from the gastric antrum of 42 subjects infected with H. pylori and 42 uninfected subjects, mucosal CCL20 mRNA and protein levels were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. CCL19 mRNA and protein levels, as well as CCL21 mRNA levels, were also measured. The CCL20 mRNA and protein levels were significantly elevated in H. pylori-positive patients and substantially decreased after successful eradication. CCL19 and CCL21 expression levels were comparable in the H. pylori-infected and the uninfected groups. The CCL20 concentrations correlated with the degree of chronic gastritis. Immunohistochemistry and the in vitro infection assay showed that CCL20 was principally produced by the gastric epithelium. CCR6-expressing cells, including CD45RO(+) memory T lymphocytes and fascin(+)-CD1a(+) immature dendritic cells, infiltrated close to the CCL20-expressing epithelial cells. The CCL20/CCR6 interaction may be involved in the development of H. pylori-associated gastritis.
30: Immunology letters, 2008 Nov 16, 121(1)
Serum amyloid A induces CCL20 secretion in mononuclear cells through MAPK (p38 and ERK1/2) signaling pathways.
[Abstract]Although the serum levels of SAA had been reported to be upregulated during inflammatory/infectious process, the role of this acute-phase protein has not been completely elucidated. In previous studies, we demonstrated that SAA stimulated the production of TNF-alpha, IL-1beta, IL-8, NO, and ROS by neutrophils and/or mononuclear cells. Herein we demonstrate that SAA induces the expression and release of CCL20 from cultured human blood mononuclear cells. We also focus on the signaling pathways triggered by SAA. In THP-1 cells SAA promotes phosphorylation of p38 and ERK1/2. Furthermore, the addition of SB203580 (p38 inhibitor) and PD98059 (ERK 1/2 inhibitor) inhibits the expression and release of CCL20 in mononuclear cells treated with SAA. Our results point to SAA as an important link of innate to adaptive immunity, once it might act on the recruitment of mononuclear cells.
31: Oral microbiology and immunology, 2008 Aug, 23(4)
CCL20 production is induced in human dental pulp upon stimulation by Streptococcus mutans and proinflammatory cytokines.
[Abstract]INTRODUCTION: Pulpitis is characterized by the marked infiltration of inflammatory cells in response to an invasion of caries-related bacteria. It is well known that chemokines regulate the trafficking of lymphocytes, and CC chemokine ligand 20 (CCL20) has been recently shown to play a crucial role in the recruitment of memory T cells and immature dendritic cells into inflammatory lesions. We previously reported that CCL20 was mainly expressed in microvascular endothelial cells and macrophages that accumulated in inflamed pulp tissues and that its specific receptor, CCR6, was expressed on infiltrated lymphocytes. However, the mechanism of CCL20 expression remains unclear. METHODS AND RESULTS: In this study, we investigated the expression of CCL20 in monocytes/macrophages, endothelial cells, and pulpal fibroblasts after stimulation with Streptococcus mutans, a representative of caries-related bacteria, or proinflammatory cytokines. CCL20 messenger RNA was detected by reverse transcription-polymerase chain reaction in inflamed pulp, but not in clinically normal pulp. By enzyme-linked immunosorbent assay, S. mutans induced a human monocytic cell line, differentiated macrophage-like THP-1 cells, and human umbilical vein endothelial cells (HUVEC) to produce an increased amount of CCL20. Lipoteichoic acid from S. mutans also elicited CCL20 production by HUVEC. Moreover, CCL20 production from pulpal fibroblasts was increased by stimulation with inetrleukin-1beta and tumor necrosis factor-alpha. CONCLUSION: Our results indicate that CCL20 expression is induced by stimulation with caries-related bacteria that have invaded deeply into the dentinal tubules as well as by proinflammatory cytokines in the inflamed pulpal lesions. It may be involved in the progression of pulpitis via accumulation of inflammatory cells.