Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
Sci Adv. 2019 May 1;5(5):eaaw5422. doi: 10.1126/sciadv.aaw5422. eCollection 2019 May.
IL-17 and TNF-α are major effector cytokines in chronic inflammation. TNF-α inhibitors have revolutionized the treatment of rheumatoid arthritis (RA), although not all patients respond, and most relapse after treatment withdrawal. This may be due to a paradoxical exacerbation of T17 responses by TNF-α inhibition. We examined the therapeutic potential of targeting cellular inhibitors of apoptosis 1 and 2 (cIAP1/2) in inflammation by its influence on human T subsets and mice with collagen-induced arthritis. Inhibition of cIAP1/2 abrogated CD4 IL-17A differentiation and IL-17 production. This was a direct effect on T cells, mediated by reducing NFATc1 expression. In mice, cIAP1/2 inhibition, when combined with etanercept, abrogated disease activity, which was associated with an increase in T and was sustained after therapy retraction. We reveal an unexpected role for cIAP1/2 in regulating the balance between T17 and T and suggest that combined therapeutic inhibition could induce long-term remission in inflammatory diseases.
IL-17 和 TNF-α 是慢性炎症的主要效应细胞因子。TNF-α 抑制剂彻底改变了类风湿关节炎（RA）的治疗方法，尽管并非所有患者都有反应，而且大多数患者在停药后都会复发。这可能是由于 TNF-α 抑制对 T17 反应的反常加剧。我们通过其对人类 T 细胞亚群和胶原诱导性关节炎小鼠的影响，研究了细胞凋亡抑制剂 1 和 2（cIAP1/2）靶向治疗炎症的潜力。cIAP1/2 的抑制消除了 CD4 IL-17A 的分化和 IL-17 的产生。这是对 T 细胞的直接影响，通过降低 NFATc1 表达来介导。在小鼠中，cIAP1/2 的抑制与依那西普联合使用可消除疾病活动，这与 T 细胞的增加有关，并且在治疗退缩后仍能持续。我们揭示了 cIAP1/2 在调节 T17 和 T 之间平衡中的意外作用，并表明联合治疗抑制可能在炎症性疾病中诱导长期缓解。
