TNFAIP3/A20 acts as master switch in TNFα blockade-driven IL-17A expression.

Anti-TNF inhibitors successfully improve life quality of patients suffering from inflammatory disease. Unfortunately, not all patients respond to anti-TNF therapy and some patients show paradoxical immune side-effects, which is poorly understood. Surprisingly, anti-TNF agents were shown to promote IL-17A production, with as yet unknown clinical implications.To investigate the molecular mechanism underlying anti-TNF driven IL-17A expression and the clinical implications of this phenomenon.FACS, RNA-sequencing, RT-qPCR, western blotting, siRNA interference and kinase-inhibitors, were used to study the molecular mechanism in isolated human CD4+ T cells from healthy donors. The clinical implication was studied in blood samples of inflammatory bowel disease (IBD) patients under anti-TNF therapy.Here we show that anti-TNF treatment results in inhibition of the anti-inflammatory molecule TNFAIP3/A20 in memory CD4+ T cells. We found an inverse relationship between TNFAIP3/A20 expression levels and IL-17A production. Inhibition of TNFAIP3/A20 promotes kinase activity of p38-MAPK and PKC, which drives IL-17A expression. Regulation of TNFAIP3/A20 expression and cognate IL-17A production in T cells is specifically mediated via TNFR2-signaling. Ex vivo, in IBD patients treated with anti-TNF, we found further evidence for an inverse relationship between TNFAIP3/A20 expression levels and IL-17A producing T cells.Anti-TNF treatment interferes in the TNFAIP3/A20 mediated anti-inflammatory feedback-loop in CD4+ T cells and promotes kinase activity. This puts TNFAIP3/A20, combined with IL-17A expression, on the map as a potential tool in predicting therapy responsiveness or side effects of anti-TNF therapy. Moreover, it provides novel targets, related to TNFAIP3/A20 activity, for superior therapeutic regimens in IBD patients.