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.
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 1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), or IL-17. IL-1beta was the most potent for stimulating the production of CCL20. CCL20 production was synergistically augmented by a combination of IL-1beta, TNF-alpha, and IL-17. In contrast, interferon-gamma suppressed IL-1beta-induced CCL20 production. IL-6, in combination with soluble IL-6 receptor (sIL-6R), did not modulate CCL20 production, whereas IL-1beta-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.


CONCLUSIONS
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.
Kawashiri
Shin-Ya
SY
Unit of Translational Medicine, Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto, Nagasaki, Japan.
Kawakami
Atsushi
A
Iwamoto
Naoki
N
Fujikawa
Keita
K
Aramaki
Toshiyuki
T
Tamai
Mami
M
Arima
Kazuhiko
K
Kamachi
Makoto
M
Yamasaki
Satoshi
S
Nakamura
Hideki
H
Tsurumoto
Toshiyuki
T
Kono
Masafumi
M
Shindo
Hiroyuki
H
Ida
Hiroaki
H
Origuchi
Tomoki
T
Eguchi
Katsumi
K
D000328:Adult; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000097:blood / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000276:immunology; D013583:Synovial Membrane / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D018501:Antirheumatic Agents; C108355:CCL20 protein, human; D054418:Chemokine CCL20; D016207:Cytokines; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma