TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis
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%...
| Príomhchruthaitheoirí: | , , , , , , , , , , , , , , |
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| Formáid: | Journal article |
| Teanga: | English |
| Foilsithe / Cruthaithe: |
Elsevier
2018
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| _version_ | 1826276513029292032 |
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| author | Peres, R Donate, P Talbot, J Cecilio, N Lobo, P Machado, C Lima, K Oliveira, R Carregaro, V Nakaya, H Cunha, T Alves-Filho, J Liew, F Louzada-Junior, P Cunha, F |
| author_facet | Peres, R Donate, P Talbot, J Cecilio, N Lobo, P Machado, C Lima, K Oliveira, R Carregaro, V Nakaya, H Cunha, T Alves-Filho, J Liew, F Louzada-Junior, P Cunha, F |
| author_sort | Peres, R |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:15:05Z |
| format | Journal article |
| id | oxford-uuid:66d9deab-b8bc-495d-9ecd-fa8d07d3fb75 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:15:05Z |
| publishDate | 2018 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:66d9deab-b8bc-495d-9ecd-fa8d07d3fb752022-03-26T18:34:32ZTGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:66d9deab-b8bc-495d-9ecd-fa8d07d3fb75EnglishSymplectic Elements at OxfordElsevier2018Peres, RDonate, PTalbot, JCecilio, NLobo, PMachado, CLima, KOliveira, RCarregaro, VNakaya, HCunha, TAlves-Filho, JLiew, FLouzada-Junior, PCunha, FRheumatoid 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. |
| spellingShingle | Peres, R Donate, P Talbot, J Cecilio, N Lobo, P Machado, C Lima, K Oliveira, R Carregaro, V Nakaya, H Cunha, T Alves-Filho, J Liew, F Louzada-Junior, P Cunha, F TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis |
| title | TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis |
| title_full | TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis |
| title_fullStr | TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis |
| title_full_unstemmed | TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis |
| title_short | TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis |
| title_sort | tgf β signalling defect is linked to low cd39 expression on regulatory t cells and methotrexate resistance in rheumatoid arthritis |
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