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

J Allergy Clin Immunol. 2018 Aug;142(2):517-529. doi: 10.1016/j.jaci.2017.11.024. Epub 2017 Dec 14.

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.

Keywords: A20; IL-17A; TNF-α; TNF-α–induced protein 3; anti-TNF; inflammatory bowel disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Biomarkers, Pharmacological / metabolism*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Female
  • Gene Expression Regulation
  • Humans
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / metabolism*
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • RNA, Small Interfering / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor alpha-Induced Protein 3 / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3 / metabolism*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*
  • Young Adult
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Inflammatory Agents
  • Biomarkers, Pharmacological
  • Interleukin-17
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Protein Kinase C
  • p38 Mitogen-Activated Protein Kinases
  • Tumor Necrosis Factor alpha-Induced Protein 3