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

被引:41
作者
Kirsch, BM
Zeyda, M
Stuhlmeier, K
Grisar, J
Smolen, JS
Watschinger, B
Stulnig, TM
Hörl, WH
Zlabinger, GJ
Säemann, MD [1 ]
机构
[1] Med Univ Vienna, Dept Internal Med 3, Clin Div Nephrol & Dialysis, Vienna, Austria
[2] Med Univ Vienna, Div Endocrinol & Metab, Dept Internal Med 3, Vienna, Austria
[3] Ludwig Boltzmann Inst Rheumatol, Vienna, Austria
[4] Med Univ Vienna, Clin Div Rheumatol, Dept Internal Med 3, Vienna, Austria
[5] Austrian Acad Sci, CeMM, Ctr Mol Med, Vienna, Austria
[6] Med Univ Vienna, Inst Immunol, Vienna, Austria
关键词
D O I
10.1186/ar1727
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-kappa B, 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.
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页码:R694 / R703
页数:10
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