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Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway

OBJECTIVE: To study the effects of different disease-modifying antirheumatic drugs (DMARD) on different events mediated by IL-15-activated lymphocytes. METHODS: Peripheral blood lymphocytes (PBL) were isolated from healthy donors and activated with IL-15 after exposure to different DMARD: leflunomid...

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Autores principales: González-Alvaro, I, Ortiz, A M, Domínguez-Jiménez, C, Aragón-Bodi, A, Sánchez, B Díaz, Sánchez-Madrid, F
Formato: Texto
Lenguaje:English
Publicado: BMJ Group 2008
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946060/
https://www.ncbi.nlm.nih.gov/pubmed/18957484
http://dx.doi.org/10.1136/ard.2008.096743
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author González-Alvaro, I
Ortiz, A M
Domínguez-Jiménez, C
Aragón-Bodi, A
Sánchez, B Díaz
Sánchez-Madrid, F
author_facet González-Alvaro, I
Ortiz, A M
Domínguez-Jiménez, C
Aragón-Bodi, A
Sánchez, B Díaz
Sánchez-Madrid, F
author_sort González-Alvaro, I
collection PubMed
description OBJECTIVE: To study the effects of different disease-modifying antirheumatic drugs (DMARD) on different events mediated by IL-15-activated lymphocytes. METHODS: Peripheral blood lymphocytes (PBL) were isolated from healthy donors and activated with IL-15 after exposure to different DMARD: leflunomide, cyclosporin A, methotrexate, mycophenolic acid, FK-506, sulphasalazine and sodium aurothiomalate. The expression of different surface molecules on the PBL was then determined by flow cytometry. Cells were also co-cultured with the monocytic cell line THP-1 and the tumour necrosis factor (TNF) concentration in the supernatant was measured after 24 h using an immunoenzyme assay. The effect of the aforementioned drugs on IL-17 production by IL-15-activated PBL was also studied. RESULTS: Treatment of PBL with leflunomide, cyclosporin A and FK-506 inhibited the IL-15-induced expression of both CD54 and CD69 by PBL, as well as TNF production in co-cultures of activated PBL and THP-1 cells. The downregulation of CD54 and CD69 in PBL was correlated with the inhibition of TNF production. Likewise, leflunomide, cyclosporin A and FK-506 all inhibited IL-17 production in IL-15-activated PBL. Interestingly, the effect of leflunomide was not reverted by the presence of uridine in the medium. In addition, leflunomide inhibited the phosphorylation of STAT6 in vitro. CONCLUSION: Inhibition of the JAK/STAT pathway may represent an additional effect of leflunomide in chronic polyarthritis because it impairs certain events that control proinflammatory TNF and IL-17 cytokine production.
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spelling pubmed-29460602010-10-04 Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway González-Alvaro, I Ortiz, A M Domínguez-Jiménez, C Aragón-Bodi, A Sánchez, B Díaz Sánchez-Madrid, F Ann Rheum Dis Basic and Translational Research OBJECTIVE: To study the effects of different disease-modifying antirheumatic drugs (DMARD) on different events mediated by IL-15-activated lymphocytes. METHODS: Peripheral blood lymphocytes (PBL) were isolated from healthy donors and activated with IL-15 after exposure to different DMARD: leflunomide, cyclosporin A, methotrexate, mycophenolic acid, FK-506, sulphasalazine and sodium aurothiomalate. The expression of different surface molecules on the PBL was then determined by flow cytometry. Cells were also co-cultured with the monocytic cell line THP-1 and the tumour necrosis factor (TNF) concentration in the supernatant was measured after 24 h using an immunoenzyme assay. The effect of the aforementioned drugs on IL-17 production by IL-15-activated PBL was also studied. RESULTS: Treatment of PBL with leflunomide, cyclosporin A and FK-506 inhibited the IL-15-induced expression of both CD54 and CD69 by PBL, as well as TNF production in co-cultures of activated PBL and THP-1 cells. The downregulation of CD54 and CD69 in PBL was correlated with the inhibition of TNF production. Likewise, leflunomide, cyclosporin A and FK-506 all inhibited IL-17 production in IL-15-activated PBL. Interestingly, the effect of leflunomide was not reverted by the presence of uridine in the medium. In addition, leflunomide inhibited the phosphorylation of STAT6 in vitro. CONCLUSION: Inhibition of the JAK/STAT pathway may represent an additional effect of leflunomide in chronic polyarthritis because it impairs certain events that control proinflammatory TNF and IL-17 cytokine production. BMJ Group 2008-10-25 /pmc/articles/PMC2946060/ /pubmed/18957484 http://dx.doi.org/10.1136/ard.2008.096743 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.
spellingShingle Basic and Translational Research
González-Alvaro, I
Ortiz, A M
Domínguez-Jiménez, C
Aragón-Bodi, A
Sánchez, B Díaz
Sánchez-Madrid, F
Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway
title Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway
title_full Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway
title_fullStr Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway
title_full_unstemmed Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway
title_short Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway
title_sort inhibition of tumour necrosis factor and il-17 production by leflunomide involves the jak/stat pathway
topic Basic and Translational Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946060/
https://www.ncbi.nlm.nih.gov/pubmed/18957484
http://dx.doi.org/10.1136/ard.2008.096743
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