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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:142

Article

Urbano, Paulo C. M.¹  Aguirre-Gamboa, Raul⁴  Ashikov, Angel²  van Heeswijk, Bennie¹  Krippner-Heidenreich, Anja⁵  Tijssen, Henk¹  Li, Yang⁴  Azevedo, Valderilio F.⁶  Smits, Lisa J. T.³  Hoentjen, Frank³  Joosten, Irma¹  Koenen, Hans J. P. M.¹ 

[1] Radboud Univ Nijmegen Med Ctr, LMI, Dept Lab Med, Geert Grootepl Zuid 10,Route 469, NL-6500 HB Nijmegen, Netherlands

[2] Radboud Univ Nijmegen Med Ctr, Dept Neurol, Nijmegen, Netherlands

[3] Radboud Univ Nijmegen Med Ctr, Dept Gastroenterol & Hepatol, Nijmegen, Netherlands

[4] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[5] Newcastle Univ, Northern Inst Canc Res, Wolfson Childhood Canc Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[6] Univ Fed Parana, Hosp Clin Curitiba, Dept Med Interna, Curitiba, Parana, Brazil

关键词: TNF-alpha;    A20;    TNF-alpha-induced protein 3;    anti-TNF;    IL-17A;    inflammatory bowel disease;   

DOI  :  10.1016/j.jaci.2017.11.024

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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