| Full text | |
| Author(s): Show less - |
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 cells Treg 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 - Emu: aquisicao dos equipamentos ivis spectrum e microscopio de excitacao por dois fotons para imagem in vivo. |
| Grantee: | Enilza Maria Espreafico |
| Support Opportunities: | Multi-user Equipment Program |