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Ann Rheum Dis 2009;68:1644-1650 doi:10.1136/ard.2008.096743
  • Basic and translational research
  • Extended report

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

  1. I González-Alvaro1,
  2. A M Ortiz1,
  3. C Domínguez-Jiménez1,
  4. A Aragón-Bodi1,
  5. B Díaz Sánchez1,
  6. F Sánchez-Madrid2
  1. 1
    Rheumatology, Hospital Universitario de la Princesa. Madrid, Spain
  2. 2
    Immunology Units, Hospital Universitario de la Princesa. Madrid, Spain
  1. Correspondence to Dr I Gonzalez-Alvaro, Rheumatology Unit, Hospital Universitario de la Princesa. Madrid, Spain; isidoro.ga{at}ser.es
  • Accepted 3 October 2008
  • Published Online First 28 October 2008

Abstract

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.

Footnotes

  • Funding This work was funded by grants FIS 04/2009, 05/2041 and G03/152 from the Instituto de Salud Carlos III to IG-A.

  • Competing interests Declared. IG-A has received unrestricted grants from Abbott Laboratories and Bristol-Myers Squibb. CD-J was supported by grants from Sanofi-Aventis and Fundación Española de Reumatología. AA-B was supported by a DIB-SER grant from the Fundación Española de Reumatología.

  • Ethics approval Ethics approval was obtained.

  • ‣ Additional supplementary table 1 is published online only at http://ard.bmj.com/content/vol68/issue10

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