A novel disease-modifying antirheumatic drug, iguratimod, ameliorates murine arthritis by blocking IL-17 signaling, distinct from methotrexate and leflunomide

• Published in: The Journal of immunology (1950) 2013-11, Vol.191 (10), p.4969-4978
• Main Authors: Luo, Qiong, Sun, Yang, Liu, Wen, Qian, Cheng, Jin, Biao, Tao, Feifei, Gu, Yanhong, Wu, Xingxin, Shen, Yan, Xu, Qiang
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Arthritis, Experimental - drug therapy; Arthritis, Experimental - metabolism; Arthritis, Rheumatoid - chemically induced; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Chromones - pharmacology; Chromones - therapeutic use; Collagen; I-kappa B Kinase - metabolism; Inflammation - drug therapy; Inflammation - immunology; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - metabolism; Isoxazoles - pharmacology; Male; Methotrexate - pharmacology; Mice; Mice, Inbred DBA; Phosphorylation - drug effects; Signal Transduction; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Synovial Membrane - drug effects; Synovial Membrane - immunology; TNF Receptor-Associated Factor 5 - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1300832

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.