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
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
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DOI：
10.3899/jrheum.090132
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发表时间：
2009-11-01
影响因子：
3.9
通讯作者：
Eguchi, Katsumi
中科院分区：
文献类型：
--
作者：
Kawashiri, Shin-Ya;Kawakami, Atsushi;Eguchi, Katsumi
Objective.趋化因子配体20（CCL 20）是趋化因子受体6（CCR 6）的选择性配体。我们在体外和体内研究了CCL 20是否在类风湿性关节炎（RA）的疾病过程中起关键作用。体外研究了促炎细胞因子和生物疾病缓解抗风湿药物（DMARD）对类风湿成纤维细胞样滑膜细胞（FLS）产生CCL 20的影响。通过在生物DMARD的治疗过程中筛选RA患者的血清CCL 20浓度来研究CCL 20的体内作用，即，英夫利昔单抗、依那西普和托西珠单抗。类风湿性FLS自发产生的CCL 20是最小的，然而，它的产生被白细胞介素1 β（IL-1 β）肿瘤坏死因子-α（TNF-α）或IL-17显著刺激。1 L-I β对刺激CCL 20的产生最有效。通过IL-1 β、TNF-α和IL-17的组合协同增强CCL 20的产生。相反，干扰素-γ抑制IL-1 β诱导的CCL 20产生。IL-6与可溶性IL-6受体（sIL-6 R）结合不良，不调节CCL 20的产生，而IL-1 β诱导的、TNF-α诱导的和IL-17诱导的产生被IL-6增加。这些生产水平在体外明显受到生物DMARD的抑制。RA患者的血清CCL 20水平显著高于对照组，而英夫利昔单抗、依那西普和托珠单抗治疗后CCL 20水平明显降低。促炎细胞因子调节FLS产生CCL 20。我们的数据表明，生物DMARD的治疗效果可能是由于抑制类风湿滑膜中的CCL 20产生。（2009年10月1日首次发布; J Rheumol 2009;36：2397-402; doi：10.3899/jrheum.090132）
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) oil 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 1 beta (IL-1 beta) tumor necrosis factor-alpha (TNF-alpha), or IL-17. 1L-I beta was the most potent for stimulating the production of CCL20. CCL20 production was synergistically augmented by a combination of IL-1 beta, TNF-alpha, and IL-17. In contrast, interferon-gamma suppressed IL-1 beta-induced CCL20 production. IL-6, ill combination with soluble IL-6 receptor (sIL-6R), did not modulate CCL20 production, whereas IL-1 beta-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 ill rheumatoid synovium. (First Release Oct 1 2009; J Rheumatol 2009;36:2397-402; doi: 10.3899/jrheum.090132)