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

• Published in: Annals of the rheumatic diseases Vol. 68; no. 10; pp. 1644 - 1650
• Main Authors: González-Alvaro, I, Ortiz, A M, Domínguez-Jiménez, C, Aragón-Bodi, A, Sánchez, B Díaz, Sánchez-Madrid, F
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.10.2009; BMJ Publishing Group; Elsevier Limited; BMJ Group
• Series: Extended report
• Subjects: Antigens, CD - biosynthesis; Antigens, Differentiation, T-Lymphocyte - biosynthesis; Antirheumatic Agents - pharmacology; Basic and Translational Research; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cells, Cultured; Coculture Techniques; Dehydrogenases; Diseases of the osteoarticular system; Drug dosages; Gangrene; Humans; Immunotherapy; Intercellular Adhesion Molecule-1 - biosynthesis; Interleukin-15 - immunology; Interleukin-17 - biosynthesis; Isoxazoles - pharmacology; Lectins, C-Type; Leflunomide; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - immunology; Lymphocytes - metabolism; Medical sciences; Pharmacology. Drug treatments; Phosphorylation; Phosphorylation - drug effects; R&D; Research & development; Signal Transduction - drug effects; STAT6 Transcription Factor - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Tumor necrosis factor-TNF; Up-Regulation - drug effects; California; United Kingdom > UK; Massachusetts; Germany; Non steroidal antiinflammatory agent; Tumor necrosis factor; Production; Rheumatology; Antirheumatic agent; Immunosuppressive agent; Leflunomide; Interleukin 17
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/ard.2008.096743

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.