RESEARCH - Inhibition of TNF and IL-17 production by Arava involves the JAK/STAT pathway

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Published Online First: 28 October 2008. doi:10.1136/ard.2008.096743

ls of the Rheumatic Diseases 2009;68:1644-1650

Extended report

Inhibition of tumour necrosis factor and IL-17 production by

leflunomide involves the JAK/STAT pathway

I González-Alvaro1, A M Ortiz1, C Domínguez-Jiménez1, A Aragón-Bodi1,

B Díaz Sánchez1, F Sánchez-Madrid2

1 Rheumatology, Hospital Universitario de la Princesa. Madrid, Spain

2 Immunology Units, Hospital Universitario de la Princesa. Madrid, Spain

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.

http://ard.bmj.com/cgi/content/abstract/68/10/1644?etoc

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