Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis
Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis
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DOI：
10.1002/art.21301
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发表时间：
2005-10-01
影响因子：
--
通讯作者：
Miyasaka, N
中科院分区：
文献类型：
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作者：
Nanki, T;Shimaoka, T;Miyasaka, N
目标。类风湿关节炎(RA)是一种与大量T细胞渗入滑膜相关的慢性炎症性疾病。积聚的T细胞表达I型细胞因子，如干扰素-γ和肿瘤坏死因子a，以及激活的炎症标志物，如CD154和诱导共刺激因子(ICOS)。据认为，趋化因子有助于T细胞在滑膜中的积聚。在本研究中，我们检测了CXCL16和CXCR6在类风湿关节炎滑膜T细胞迁移和刺激中的作用。免疫组织化学、逆转录-聚合酶链式反应、Western blotting和/或流式细胞术检测CXCL16和CXCR6的表达。趋化性小室用于评估迁移活性。采用酶联免疫吸附试验检测细胞产生干扰素-γ的情况。观察抗CXCL16单抗对胶原性关节炎(CIA)小鼠的治疗作用。CXCL16在RA滑膜中有表达。滑膜T细胞表达CXCR6的频率高于外周血。此外，CXCR6阳性的滑膜T细胞表达CD154和ICOS的频率高于CXCR6阴性的T细胞。IL-15刺激可上调外周血T细胞表面CXCR6的表达，CXCL16刺激可诱导IL-15刺激的T细胞迁移，促进干扰素-γ的产生。此外，抗CXCL16单抗还能显著降低CIA小鼠的临床关节炎评分，减少滑膜中炎性细胞的浸润和骨质破坏。结果表明，CXCL16在RA滑膜中T细胞的聚集和刺激中起重要作用，提示CXCL16可能成为RA新疗法的靶向分子。
Objective. Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with massive T cell infiltration into the synovium. The accumulated T cells express type I cytokines, such as interferon-gamma (IFN gamma) and tumor necrosis factor a, and activated markers of inflammation, such as CD154 and inducible costimulator (ICOS). It is thought that chemokines contribute to T cell accumulation in the synovium. In this study, we examined the role of CXCL16 and CXCR6 in T cell migration and stimulation in RA synovium.Methods. Expression of CXCL16 and CXCR6 was analyzed by immunohistochemistry, reverse transcription-polymerase chain reaction, Western blotting, and/or flow cytometry. Migration activity was assessed using a chemotaxis chamber. IFN-gamma production was analyzed by enzyme-linked immunosorbent assay. The effect of anti-CXCL16 monoclonal antibody on murine collagen-induced arthritis (CIA) was evaluated.Results. CXCL16 was expressed in RA synovium. CXCR6 was expressed more frequently on synovial T cells than in peripheral blood. Moreover, CXCR6-positive synovial T cells more frequently expressed CD154 and ICOS than did CXCR6-negative T cells. Stimulation with interleukin-15 (IL-15) up-regulated the expression of CXCR6 on peripheral blood T cells, and then stimulation with CXCL16 induced migration of IL-15-stimulated T cells and enhanced IFN gamma production. Furthermore, anti-CXCL16 monoclonal antibody significantly reduced the clinical arthritis score and reduced infiltration of inflammatory cells and bone destruction in the synovium of mice with CIA.Conclusion. Our results indicate that CXCL16 plays an important role in T cell accumulation and stimulation in RA synovium and suggest that CXCL16 could be a target molecule in new therapies for RA.