Lookup NU author(s): Dr Anja Krippner-Heidenreich
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2017 American Academy of Allergy, Asthma & Immunology. 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-ň-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.
Author(s): Urbano PCM, Aguirre-Gamboa R, Ashikov A, van Heeswijk B, Krippner-Heidenreich A, Tijssen H, Li Y, Azevedo VF, Smits LJT, Hoentjen F, Joosten I, Koenen HJPM
Publication type: Article
Publication status: Published
Journal: Journal of Allergy and Clinical Immunology
Print publication date: 01/08/2018
Online publication date: 14/12/2017
Acceptance date: 06/11/2017
Date deposited: 23/03/2018
ISSN (print): 0091-6749
ISSN (electronic): 1097-6825
Publisher: Mosby Inc.
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