okadaic-acid and teriflunomide

Leflunomide is a novel immunosuppressive and antiinflammatory agent currently being tested for treatment of autoimmune diseases and transplant rejection. NF-kappa B is a transcription factor activated in response to a wide variety of inflammatory stimuli, including TNF, but whether leflunomide blocks NF-kappa B activation is not known. In the present report we demonstrate that treatment of a human T cell line (Jurkat) with leflunomide blocks TNF-mediated NF-kappa B activation in a dose- and time-dependent manner, with maximum inhibition at 5-10 microM. Inhibition was not restricted to TNF-induced activation, because leflunomide also inhibited NF-kappa B activation induced by other inflammatory agents, including phorbol ester, LPS, H2O2, okadaic acid, and ceramide. Leflunomide blocked the degradation of I kappa B alpha and subsequent nuclear translocation of the p65 subunit, steps essential for NF-kappa B activation. This correlated with inhibition of dual specificity-mitogen-activated protein kinase kinase as well as an Src protein tyrosine kinase, p56lck, by leflunomide. Reducing agents did not reverse the effect of leflunomide. Leflunomide also suppressed the TNF-activated NF-kappa B-dependent reporter gene expression. Our results thus indicate that leflunomide is a potent inhibitor of NF-kappa B activation induced by a wide variety of inflammatory stimuli, and this provides the molecular basis for its anti-inflammatory and immunosuppressive effects.

Topics: Aniline Compounds; Biological Transport; Cell Nucleus; Ceramides; Chloramphenicol O-Acetyltransferase; Crotonates; Dithiothreitol; DNA-Binding Proteins; Enzyme Activation; Gene Expression Regulation; Genes, MDR; Genes, Reporter; Host Cell Factor C1; Humans; Hydrogen Peroxide; Hydroxybutyrates; I-kappa B Proteins; Immunosuppressive Agents; Isoxazoles; Leflunomide; Lipopolysaccharides; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Mitogen-Activated Protein Kinase Kinases; NF-kappa B; NF-kappa B p50 Subunit; NF-KappaB Inhibitor alpha; Nitriles; Octamer Transcription Factor-1; Okadaic Acid; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Tetradecanoylphorbol Acetate; Toluidines; Transcription Factor AP-1; Transcription Factor RelA; Transcription Factors; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha