Details

Autor(en) / Beteiligte

• Peres, Raphael S.
• Donate, Paula B.
• Talbot, Jhimmy
• Cecilio, Nerry T.
• Lobo, Patricia R.
• Machado, Caio C.
• Lima, Kalil W.A.
• Oliveira, Rene D.
• Carregaro, Vanessa
• Nakaya, Helder I.
• Cunha, Thiago M.
• Alves-Filho, José Carlos
• Liew, Foo Y.
• Louzada-Junior, Paulo
• Cunha, Fernando Q.

Titel

TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis

Ist Teil von

• Journal of autoimmunity, 2018-06, Vol.90, p.49-58

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• Rheumatoid arthritis (RA) is an autoimmune arthropathy characterized by chronic articular inflammation. Methotrexate (MTX) remains the first-line therapy for RA and its anti-inflammatory effect is associated with the maintenance of high levels of extracellular adenosine (ADO). Nonetheless, up to 40% of RA patients are resistant to MTX treatment and this is linked to a reduction of CD39 expression, an ectoenzyme involved in the generation of extracellular ADO by ATP metabolism, on circulating regulatory T cells (Tregs). However, the mechanism mediating the reduction of CD39 expression on Tregs is unknown. Here we demonstrated that the impairment in TGF-β signalling lead to the reduction of CD39 expression on Tregs that accounts for MTX resistance. TGF-β increases CD39 expression on Tregs via the activation of TGFBRII/TGFBRI, SMAD2 and the transcription factor CREB, which is activated in a p38-dependent manner and induces CD39 expression by promoting ENTPD1 gene transcription. Importantly, unresponsive patients to MTX (UR-MTX) show reduced expression of TGFBR2 and CREB1 and decreased levels of p-SMAD2 and p-CREB in Tregs compared to MTX-responsive patients (R-MTX). Furthermore, RA patients carrying at least one mutant allele for rs1431131 (AT or AA) of the TGFBR2 gene are significantly (p = 0.0006) associated with UR-MTX. Therefore, we have uncovered a molecular mechanism for the reduced CD39 expression on Tregs, and revealed potential targets for therapeutic intervention for MTX resistance. [Display omitted] •Low CD39 expression on Tregs is a potential biomarker for MTX resistance in RA.•We show here that impairment of TGF-β signalling reduces CD39 expression.•TGF-β-induced CD39 expression is triggered via TGFBRII/TGFBRI, SMAD2 and CREB.•MTX resistance is associated with SNP rs1431131 in the TGFBR2 gene.