title: 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.affiliation: Department of Internal Medicine III/Clinical Division of Nephrology, Medical University of Vienna, Vienna, Austria. bernhard.kirsch@meduniwien.ac.at
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Kirsch
authors.forename: Maximilian
authors.initials: M
authors.lastname: Zeyda
authors.forename: Karl
authors.initials: K
authors.lastname: Stuhlmeier
authors.forename: Johannes
authors.initials: J
authors.lastname: Grisar
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Bruno
authors.initials: B
authors.lastname: Watschinger
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stulnig
authors.forename: Walter H
authors.initials: WH
authors.lastname: Hörl
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Zlabinger
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Säemann
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003437:Crotonates; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism / Q000494:pharmacology*; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology*; D000077339:Leflunomide; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009570:Nitriles; D014052:Toluidines
chemical_list: D000814:Aniline Compounds; D003437:Crotonates; D006885:Hydroxybutyrates; D007555:Isoxazoles; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D000077339:Leflunomide