Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1126/sciadv.aaw5422

Type

Journal article

Journal

Sci adv

Publication Date

05/2019

Volume

5

Keywords

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