Kanagawa Hiroya, Niki Yasuo, Kobayashi Tami, Sato Yuiko, Katsuyama Eri, Fujie Atsuhiro, Hao Wu, Miyamoto Kana, Tando Toshimi, Watanabe Ryuichi, Morita Mayu, Morioka Hideo, Matsumoto Morio, Toyama Yoshiaki, Miyamoto Takeshi
Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
J Bone Miner Metab. 2015 Mar;33(2):135-41. doi: 10.1007/s00774-014-0575-9. Epub 2014 Mar 15.
Rheumatoid arthritis (RA) is a multifactorial disease caused by genetic and environmental factors: however, precise molecular mechanisms underlying its pathogenesis remain largely unknown. Treatment of RA patients with disease-modifying biological agents occasionally promotes Mycobacterium tuberculosis infection or recurrence of M. tuberculosis, although how infection promotes arthritis has not been characterized. Here, we found that arthritis phenotypes in a collagen-induced mouse model were evident only when killed M. tuberculosis was co-administered. Treatment of cultured macrophages with killed M. tuberculosis promoted production of IL-6, a major inflammatory cytokine in RA patients, while similar treatment of TLR2-deficient macrophages failed to induce IL-6 expression. Arthritis scores, joint destruction, and serum IL-6 levels were all significantly ameliorated in TLR2-deficient compared with wild-type mice, even in animals treated with killed M. tuberculosis. These results suggest that M. tuberculosis infection enhances arthritis development and that TLR2 could serve as a therapeutic target for some forms of the disease.
类风湿性关节炎（RA）是一种由遗传和环境因素引起的多因素疾病；然而，其发病机制背后的确切分子机制仍 largely 未知。用改善病情的生物制剂治疗 RA 患者偶尔会促进结核分枝杆菌感染或结核分枝杆菌复发，尽管感染如何促进关节炎尚未明确。在此，我们发现，仅在同时给予灭活结核分枝杆菌时，胶原诱导的小鼠模型中的关节炎表型才明显。用灭活结核分枝杆菌处理培养的巨噬细胞可促进 IL-6 的产生，IL-6 是 RA 患者的一种主要炎性细胞因子，而对 TLR2 缺陷型巨噬细胞进行类似处理则未能诱导 IL-6 表达。与野生型小鼠相比，TLR2 缺陷型小鼠的关节炎评分、关节破坏和血清 IL-6 水平均显著改善，即使在接受灭活结核分枝杆菌治疗的动物中也是如此。这些结果表明，结核分枝杆菌感染会增强关节炎的发展，并且 TLR2 可作为该疾病某些形式的治疗靶点。
