A Novel Disease-Modifying Antirheumatic Drug, Iguratimod, Ameliorates Murine Arthritis by Blocking IL-17 Signaling, Distinct from Methotrexate and Leflunomide
A Novel Disease-Modifying Antirheumatic Drug, Iguratimod, Ameliorates Murine Arthritis by Blocking IL-17 Signaling, Distinct from Methotrexate and Leflunomide
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与甲氨蝶呤和来氟米特不同，艾拉莫德是一种新型缓解疾病的抗风湿药物，通过阻断 IL-17 信号传导来改善小鼠关节炎
DOI：
10.4049/jimmunol.1300832
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发表时间：
2013-11-15
影响因子：
4.4
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Luo, Qiong;Sun, Yang;Xu, Qiang
伊古拉莫德是一种新型的缓解疾病的抗风湿药物，现已在中国和日本的临床使用，已被证实是一种高效、安全的类风湿关节炎治疗药物。iguratimod的抗关节炎机制，特别是与经典的缓解疾病的抗风湿药物相比，尚未阐明。在这项研究中，我们进行了iguratimod和两个参考药物，甲氨蝶呤和来氟米特的抗关节炎作用的比较分析。我们发现，iguratimod剂量依赖性和有效地抑制胶原诱导的关节炎中滑膜的关节炎性炎症，并主要靶向IL-17信号传导。与其在体内的作用一致，iguratimod显著抑制了培养的成纤维细胞样滑膜细胞中由IL-17触发的各种促炎因子的表达。iguratimod对IL-17信号传导的抑制进一步与相关基因mRNA稳定性的降低和MAPK磷酸化的减少有关。艾拉莫德主要靶向Act 1，以破坏滑膜细胞IL-17通路中Act 1与TRAF 5和IKKi之间的相互作用。总之，我们的研究结果表明，iguratimod通过其独特的抑制成纤维细胞样滑膜细胞中的IL-17信号传导，在关节炎中产生强烈的改善。iguratimod的这一特征不同于甲氨蝶呤和来氟米特。本研究有助于进一步了解艾拉莫德治疗类风湿关节炎的独特机制。
Iguratimod, a novel disease-modifying antirheumatic drug, which is now used in clinics in China and Japan, has been confirmed as a highly efficacious and safe drug for rheumatoid arthritis therapy. The antiarthritic mechanism of iguratimod, especially compared with that of the classical disease-modifying antirheumatic drugs, has not been elucidated. In this study, we conducted a comparative analysis of the antiarthritic effects of iguratimod and two reference drugs, methotrexate and leflunomide. We found that iguratimod dose dependently and potently inhibited arthritic inflammation of the synovium in collagen-induced arthritis and predominantly targeted IL-17 signaling. Consistent with its effects in vivo, iguratimod significantly suppressed the expression of various proinflammatory factors triggered by IL-17 in the cultured fibroblast-like synoviocytes. The inhibition of IL-17 signaling by iguratimod was further linked to a decrease in the mRNA stability of related genes and a reduction in phosphorylation of MAPKs. Iguratimod mainly targets Act1 to disrupt the interaction between Act1 and TRAF5 and IKKi in the IL-17 pathway of synoviocytes. Together, our results suggest that iguratimod yields a strong improvement in arthritis via its unique suppression of IL-17 signaling in fibroblast-like synoviocytes. This feature of iguratimod is different from those of methotrexate and leflunomide. This study may be helpful for further understanding the unique antiarthritic mechanism of iguratimod in patients with rheumatoid arthritis.