Interleukin-6 Blockade Suppresses Autoimmune Arthritis in Mice by the Inhibition of Inflammatory Th17 Responses
Interleukin-6 Blockade Suppresses Autoimmune Arthritis in Mice by the Inhibition of Inflammatory Th17 Responses
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DOI：
10.1002/art.24126
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发表时间：
2008-12-01
影响因子：
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通讯作者：
Naka, Tetsuji
中科院分区：
文献类型：
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作者：
Fujimoto, Minoru;Serada, Satoshi;Naka, Tetsuji
目标。通过比较抗IL-6受体(抗IL-6R)单抗和可溶性肿瘤坏死因子(STNFR)-Fc融合蛋白对胶原诱导性关节炎(CIA)辅助性T细胞分化的影响，探讨IL-6阻断自身免疫性关节炎的机制。用11型胶原(CII)免疫DBA/1小鼠诱导关节炎，不治疗或用抗IL-6R单抗或TNFR-Fc治疗。分析小鼠关节炎形成过程中辅助性T细胞的分化和细胞因子的表达。CII免疫主要增加Th17细胞的频率，而不是Th1细胞。免疫后FoxP3+Treg细胞频率也明显增加。用抗IL-6R单抗在第0天用CIA处理小鼠可显著抑制Th17细胞的诱导和关节炎的发生，但在第14天用该抗体处理不能同时抑制Th17分化和关节炎的发生。相反，从第0天到第14天使用CIA的TNFR-FC治疗既没有抑制Th17分化也没有抑制关节炎，但从第21天到第35天的治疗成功地改善了关节炎，但没有抑制Th17的诱导。两种抗体治疗均不增加Treg细胞的频率。我们的结果表明，阻断IL-6对CIA的保护作用与抑制Th17分化有关，而阻断肿瘤坏死因子对CIA的保护作用与抑制Th17分化有关。我们的研究结果提示，阻断IL-6治疗类风湿关节炎也可能涉及一种与阻断肿瘤坏死因子不同的治疗机制，因此对于肿瘤坏死因子阻断无效的患者来说，可能是一种替代治疗方法。
Objective. To investigate the mechanism of interleukin-6 (IL-6) blockade in autoimmune arthritis, by comparing the effect of anti-IL-6 receptor (anti-IL-6R) monoclonal antibody (mAb) treatment with the effect of soluble tumor necrosis factor (sTNFR)-Fc fusion protein treatment on T helper cell differentiation in collagen-induced arthritis (CIA).Methods. DBA/1 mice were immunized with type 11 collagen (CII) to induce arthritis and were left untreated or were treated with anti-IL-6R mAb or TNFR-Fc. T helper cell differentiation and cytokine expression during the development of arthritis in these mice were analyzed.Results. Immunization with CII predominantly increased the frequency of Th17 cells rather than Th1 cells. The frequency of FoxP3+ Treg cells was also increased after immunization. Treatment of mice with CIA with anti-IL-6R mAb on day 0 markedly suppressed the induction of Th17 cells and arthritis development, but treatment with this antibody on day 14 failed to suppress both Th17 differentiation and arthritis. In contrast, treatment of mice with CIA with TNFR-Fc from day 0 to day 14 suppressed neither Th17 differentiation nor arthritis, but treatment from day 21 to day 35 successfully ameliorated arthritis without inhibiting Th17 induction. Neither antibody treatment increased the frequency of Treg cells.Conclusion. Our results indicate that the protective effect of IL-6 blockade, but not tumor necrosis factor (TNF) blockade, in CIA correlates with the inhibition of Th17 differentiation. Our findings suggest that IL-6 blockade in rheumatoid arthritis in human is also likely to involve a therapeutic mechanism distinct from that of TNF blockade and thus may represent an alternative therapy for patients in whom the disease is refractory to TNF blockade.