Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of allergy and clinical immunology, 2018-08, Vol.142 (2), p.517-529

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. We sought to investigate the molecular mechanism underlying anti-TNF–driven IL-17A expression and the clinical implications of this phenomenon. 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. 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. 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.