Nowell Mari A, Richards Peter J, Horiuchi Sankichi, Yamamoto Naoki, Rose-John Stefan, Topley Nicholas, Williams Anwen S, Jones Simon A
Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom.
J Immunol. 2003 Sep 15;171(6):3202-9. doi: 10.4049/jimmunol.171.6.3202.
Studies in IL-6-deficient (IL-6(-/-)) mice highlight that IL-6 contributes to arthritis progression. However, the molecular mechanism controlling its activity in vivo remains unclear. Using an experimental arthritis model in IL-6(-/-) mice, we have established a critical role for the soluble IL-6R in joint inflammation. Although intra-articular administration of IL-6 itself was insufficient to reconstitute arthritis within these mice, a soluble IL-6R-IL-6 fusion protein (HYPER-IL-6) restored disease activity. Histopathological assessment of joint sections demonstrated that HYPER-IL-6 increased arthritis severity and controlled intrasynovial mononuclear leukocyte recruitment through the CC-chemokine CCL2. Activation of synovial fibroblasts by soluble IL-6R and IL-6 emphasized that these cells may represent the source of CCL2 in vivo. Specific blockade of soluble IL-6R signaling in wild-type mice using soluble gp130 ameliorated disease. Consequently, soluble IL-6R-mediated signaling represents a promising therapeutic target for the treatment of rheumatoid arthritis.
对白细胞介素-6缺陷（IL-6(-/-)）小鼠的研究表明，IL-6会促进关节炎的发展。然而，控制其体内活性的分子机制仍不清楚。利用IL-6(-/-)小鼠的实验性关节炎模型，我们确定了可溶性IL-6受体在关节炎症中的关键作用。尽管在这些小鼠关节内注射IL-6本身不足以重建关节炎，但可溶性IL-6受体-IL-6融合蛋白（HYPER-IL-6）恢复了疾病活性。关节切片的组织病理学评估表明，HYPER-IL-6增加了关节炎的严重程度，并通过CC趋化因子CCL2控制滑膜内单核白细胞的募集。可溶性IL-6受体和IL-6对滑膜成纤维细胞的激活强调，这些细胞可能是体内CCL2的来源。使用可溶性gp130特异性阻断野生型小鼠中的可溶性IL-6受体信号可改善疾病。因此，可溶性IL-6受体介导的信号代表了类风湿性关节炎治疗的一个有前景的治疗靶点。
