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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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Peres, Raphael S. [1, 2] ; Donate, Paula B. [1] ; Talbot, Jhimmy [1] ; Cecilio, Nerry T. [1] ; Lobo, Patricia R. [3] ; Machado, Caio C. [3] ; Lima, Kalil W. A. [1] ; Oliveira, Rene D. [3] ; Carregaro, Vanessa [4] ; Nakaya, I, Helder ; Cunha, Thiago M. [1] ; Alves-Filho, Jose Carlos [1] ; Liew, Foo Y. [5, 6] ; Louzada-Junior, Paulo [3] ; Cunha, Fernando Q. [1]
Total Authors: 15
Affiliation:
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil
[2] Univ Oxford, Kennedy Inst Rheumatol, Oxford - England
[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Ribeirao Preto - Brazil
[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto - Brazil
[5] Soochow Univ, Sch Biol & Basic Med Sci, Suzhou 215006 - Peoples R China
[6] Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow, Lanark - Scotland
Total Affiliations: 6
Document type: Journal article
Source: Journal of Autoimmunity; v. 90, p. 49-58, JUN 2018.
Web of Science Citations: 7
Abstract

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-beta signalling lead to the reduction of CD39 expression on Tregs that accounts for MTX resistance. TGF-beta 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 ENTPDI gene transcription. Importantly, unresponsive patients to MTX (UR-MTX) show reduced expression of TGFBR2 and CREBI 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. (C) 2018 Elsevier Ltd. All rights reserved. (AU)

FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 12/10438-0 - Association of CD39 expression on Treg cells with the therapeutic efficacy of methotrexate in treatment of rheumatoid arthritis
Grantee:Raphael Sanches Peres
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 09/54014-7 - Acquisition of a biophotonic imaging system and a multiphoton microscopy system for in vivo imaging
Grantee:Enilza Maria Espreafico
Support Opportunities: Multi-user Equipment Program