TNF-?–induced protein 3 (TNFAIP3)/A20 acts as a master switch in TNF-? blockade–driven IL-17A expression - 04/08/18
Abstract |
Background |
Anti-TNF inhibitors successfully improve the quality of life of patients with inflammatory disease. Unfortunately, not all patients respond to anti-TNF therapy, and some patients show paradoxical immune side effects, which are poorly understood. Surprisingly, anti-TNF agents were shown to promote IL-17A production with as yet unknown clinical implications.
Objective |
We sought to investigate the molecular mechanism underlying anti-TNF–driven IL-17A expression and the clinical implications of this phenomenon.
Methods |
Fluorescence-activated cell sorting, RNA sequencing, quantitative real-time PCR, Western blotting, small interfering RNA interference, and kinase inhibitors were used to study the molecular mechanisms in isolated human CD4+ T cells from healthy donors. The clinical implication was studied in blood samples of patients with inflammatory bowel disease (IBD) receiving anti-TNF therapy.
Results |
Here we show that anti-TNF treatment results in inhibition of the anti-inflammatory molecule TNF-α–induced protein 3 (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 mitogen-activated protein kinase and protein kinase C, which drives IL-17A expression. Regulation of TNFAIP3/A20 expression and cognate IL-17A production in T cells are specifically mediated through TNF receptor 2 signaling. Ex vivo, in patients with IBD treated with anti-TNF, we found further evidence for an inverse relationship between TNFAIP3/A20 expression levels and IL-17A–producing T cells.
Conclusion |
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 for 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 patients with IBD.
Le texte complet de cet article est disponible en PDF.Key words : TNF-α, A20, TNF-α–induced protein 3, anti-TNF, IL-17A, inflammatory bowel disease
Abbreviations used : APC, DC, DEG, FACS, IBD, MAPK, mTNF, NF-κB, PKC, RA, rhIL-2, rhTNF-α, RNA-seq, RT-qPCR, siRNA, SNP, TCR, Tmem, Tnaive, TNFAIP3, TNFR
Plan
| The study and P.C.M.U. were supported by grant no. 11920/13-0 provided by the Brazilian mobility program Science Without Borders. |
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| Disclosure of potential conflict of interest: V. F. Azevedo received board membership from Americas Health Foundation; consultancy fees from Pfizer, AbbVie, and Janssen-Cylag; payment for lectures from Pfizer, Janssen, AbbVie, and Roche; payment for development of educational materials; and travel expenses from Janssen-Cylag and AbbVie. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 2
P. 517-529 - août 2018 Retour au numéro
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