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 TH17 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 TH 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 Tregs and was sustained after therapy retraction. We reveal an unexpected role for cIAP1/2 in regulating the balance between TH17 and Tregs and suggest that combined therapeutic inhibition could induce long-term remission in inflammatory diseases.
Journal article
Sci Adv
05/2019
5
Animals, Arthritis, Experimental, Arthritis, Rheumatoid, Autoimmunity, Baculoviral IAP Repeat-Containing 3 Protein, Cells, Cultured, Dipeptides, Down-Regulation, Drug Synergism, Humans, Indoles, Inhibitor of Apoptosis Proteins, Interleukin-17, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, T-Lymphocytes, Regulatory, Th17 Cells, Tumor Necrosis Factor Inhibitors, Tumor Necrosis Factor-alpha, Ubiquitin-Protein Ligases