CCL20 produced in the cytokine network of rheumatoid arthritis recruits CCR6+ mononuclear cells and enhances the production of IL-6.
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.
Tanida
Shimei
S
Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Yoshitomi
Hiroyuki
H
Nishitani
Kohei
K
Ishikawa
Masahiro
M
Kitaori
Toshiyuki
T
Ito
Hiromu
H
Nakamura
Takashi
T
D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000096:biosynthesis*; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D054399:Receptors, CCR6 / Q000032:analysis*; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C106311:CCR6 protein, human; D054418:Chemokine CCL20; D016207:Cytokines; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D054399:Receptors, CCR6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma