The active metabolite of leflunomide, A77 1726, interferes with dendritic cell function.

Abstract

Leflunomide, a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA), exhibits anti-inflammatory, antiproliferative and immunosuppressive effects. Although most of the beneficial effects of leflunomide have been attributed to its antimetabolite activity, mainly in T cells, other targets accounting for its potency might still exist. Because of mounting evidence for a prominent role of dendritic cells (DCs) in the initiation and maintenance of the immune response in RA, we analyzed the effect of the active metabolite of leflunomide (A77 1726; LEF-M) on phenotype and function of human myleloid DCs at several stages in their life cycle. Importantly, DCs differentiated in the presence of LEF-M exhibited an altered phenotype, with largely reduced surface expression of the critical co-stimulatory molecules CD40 and CD80. Furthermore, treatment of DCs during the differentiation or maturation phase with LEF-M aborted successful DC maturation. Exogenous addition of uridine revealed that DC modulation by LEF-M was independent of its proposed ability as an antimetabolite. In addition, the ability of DCs to initiate T-cell proliferation and to produce the proinflammatory cytokines IL-12 and tumour necrosis factor-alpha was markedly impaired by LEF-M treatment. As a molecular mechanism, transactivation of nuclear factor-kappaB, an transcription factor essential for proper DC function, was completely suppressed in DCs treated with LEF-M. These data indicate that interference with several aspects of DC function could significantly contribute to the beneficial effects of leflunomide in inflammatory diseases, including RA.

• Authors: Bernhard M Kirsch, Maximilian Zeyda, Karl Stuhlmeier, Johannes Grisar, Josef S Smolen, Bruno Watschinger, Thomas M Stulnig, Walter H Hörl, Gerhard J Zlabinger, Marcus D Säemann
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 7 Issue 3 Pg. R694-703 ( 2005) ISSN: 1478-6362 [Electronic] England
• PMID: 15899055 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Crotonates
• Hydroxybutyrates
• Isoxazoles
• Nitriles
• Toluidines
• teriflunomide
• Leflunomide

Topics

• Aniline Compounds (metabolism, pharmacology)
• Cell Differentiation (drug effects, physiology)
• Cells, Cultured
• Crotonates
• Dendritic Cells (cytology, drug effects, physiology)
• Humans
• Hydroxybutyrates (metabolism, pharmacology)
• Isoxazoles (metabolism, pharmacology)
• Leflunomide
• Leukocytes, Mononuclear (cytology, drug effects, physiology)
• Nitriles
• Toluidines