Nanki Toshihiro, Shimaoka Takeshi, Hayashida Kenji, Taniguchi Ken, Yonehara Shin, Miyasaka Nobuyuki
Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Yushima, Tokyo, Japan.
Arthritis Rheum. 2005 Oct;52(10):3004-14. doi: 10.1002/art.21301.
Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with massive T cell infiltration into the synovium. The accumulated T cells express type 1 cytokines, such as interferon-gamma (IFNgamma) and tumor necrosis factor alpha, 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.
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. IFNgamma production was analyzed by enzyme-linked immunosorbent assay. The effect of anti-CXCL16 monoclonal antibody on murine collagen-induced arthritis (CIA) was evaluated.
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 IFNgamma 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.
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.
类风湿关节炎（RA）是一种慢性炎症性疾病，与大量T细胞浸润滑膜有关。积聚的T细胞表达1型细胞因子，如干扰素-γ（IFNγ）和肿瘤坏死因子α，以及炎症激活标志物，如CD154和诱导性共刺激分子（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，我们研究了CXCL16和CXCR6在RA滑膜中T细胞迁移和刺激中的作用。
通过免疫组织化学、逆转录-聚合酶链反应、蛋白质免疫印迹和/或流式细胞术分析CXCL16和CXCR6的表达。使用趋化室评估迁移活性。通过酶联免疫吸附测定分析IFNγ的产生。评估抗CXCL16单克隆抗体对小鼠胶原诱导性关节炎（CIA）的影响。
CXCL16在RA滑膜中表达。CXCR6在滑膜T细胞上的表达比在外周血中更频繁。此外，CXCR6阳性滑膜T细胞比CXCR6阴性T细胞更频繁地表达CD154和ICOS。用白细胞介素-15（IL-15）刺激上调外周血T细胞上CXCR6的表达，然后用CXCL16刺激诱导IL-15刺激的T细胞迁移并增强IFNγ的产生。此外，抗CXCL16单克隆抗体显著降低了CIA小鼠的临床关节炎评分，并减少了滑膜中炎性细胞的浸润和骨破坏。
我们的结果表明，CXCL16在RA滑膜中T细胞积聚和刺激中起重要作用，并提示CXCL16可能是RA新疗法中的一个靶分子。
