TNF-alpha-induced protein 3 (TNFAIP3)/A20 acts as a master switch in TNF-alpha blockade-driven IL-17A expression

Paulo C. M. Urbano, Raul Aguirre-Gamboa, Angel Ashikov, Bennie van Heeswijk, Anja Krippner-Heidenreich, Henk Tijssen, Yang Li, Valderilio F. Azevedo, Lisa J. T. Smits, Frank Hoentjen, Irma Joosten, Hans J. P. M. Koenen*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    20 Citations (Scopus)

    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-alpha-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 1 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.

    Original languageEnglish
    Pages (from-to)517-529
    Number of pages13
    JournalJournal of Allergy and Clinical Immunology
    Volume142
    Issue number2
    DOIs
    Publication statusPublished - Aug-2018

    Keywords

    • TNF-alpha
    • A20
    • TNF-alpha-induced protein 3
    • anti-TNF
    • IL-17A
    • inflammatory bowel disease
    • NF-KAPPA-B
    • INFLAMMATORY-BOWEL-DISEASE
    • KINASE-C-THETA
    • GENOME-WIDE ASSOCIATION
    • NECROSIS-FACTOR-ALPHA
    • RHEUMATOID-ARTHRITIS
    • AUTOIMMUNE ENCEPHALOMYELITIS
    • CELL ACTIVATION
    • TH17 CELLS
    • T-CELLS

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