cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing T_regs

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 T_H17 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_H 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_regs and was sustained after therapy retraction. We reveal an unexpected role for cIAP1/2 in regulating the balance between T_H17 and T_regs and suggest that combined therapeutic inhibition could induce long-term remission in inflammatory diseases.