okadaic-acid and vesnarinone

Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-kappa B in these responses, we hypothesized that vesnarinone must modulate NF-kappa B activation. We investigated the effect of vesnarinone on NF-kappa B activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-kappa B in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of I kappa B alpha, an inhibitor of NF-kappa B. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-kappa B activation in a variety of cells. NF-kappa B-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-kappa B activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-kappa B-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-kappa B-inducing kinase sites by vesnarinone, thus suppressing NF-kappa B reporter gene expression. Vesnarinone also blocked NF-kappa B activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-kappa B and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone's ability to suppress inflammation, immunomodulation, and growth regulation.

Topics: Apoptosis; Biological Transport; Ceramides; Chloramphenicol O-Acetyltransferase; DNA; DNA-Binding Proteins; Enzyme Activation; Enzyme Inhibitors; Genes, MDR; Genes, Reporter; HeLa Cells; Humans; Hydrogen Peroxide; I-kappa B Proteins; Immunosuppressive Agents; JNK Mitogen-Activated Protein Kinases; Jurkat Cells; Lipid Peroxidation; Lipopolysaccharides; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; NF-kappa B; NF-kappa B p50 Subunit; NF-KappaB Inhibitor alpha; Okadaic Acid; Phosphorylation; Protein Binding; Pyrazines; Quinolines; Signal Transduction; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Transcription Factor RelA; Tumor Necrosis Factor-alpha; U937 Cells; Uridine