Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / immunology
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Arthritis, Rheumatoid / drug therapy
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Arthritis, Rheumatoid / immunology*
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Arthritis, Rheumatoid / pathology
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Autoimmunity / drug effects*
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Baculoviral IAP Repeat-Containing 3 Protein / antagonists & inhibitors*
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Cells, Cultured
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Dipeptides / pharmacology
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Down-Regulation
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Drug Synergism
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Humans
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Indoles / pharmacology
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Interleukin-17 / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred DBA
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T-Lymphocytes, Regulatory / immunology*
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Th17 Cells / immunology
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Tumor Necrosis Factor Inhibitors / therapeutic use
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Ubiquitin-Protein Ligases / antagonists & inhibitors*
Substances
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Dipeptides
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GT13072
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IL17A protein, human
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Il17a protein, mouse
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Indoles
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Inhibitor of Apoptosis Proteins
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Interleukin-17
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Tumor Necrosis Factor Inhibitors
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Tumor Necrosis Factor-alpha
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BIRC2 protein, human
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BIRC3 protein, human
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Baculoviral IAP Repeat-Containing 3 Protein
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Birc2 protein, mouse
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Birc3 protein, mouse
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Ubiquitin-Protein Ligases