Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase,and apoptosis

Vesnarinone, a synthetic quinolinone derivative used in the treatment of ca rdiac failure, exhibits immunomodulatory, antiinflammatory, 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-kap pa B activation induced by inflammatory agents. Vesnarinone blocked TNF-ind uced activation of NF-kappa B in a concentration- and time-dependent manner , This effect was mediated through inhibition of phosphorylation and degrad ation of I kappa B alpha; an inhibitor of NF-kappa B, The effects of vesnar inone were not cell type specific, as it blocked TNF-indced NF-kappa B acti vation in a variety of cells. NF-kappa B dependent reporter gene transcript ion activated by TNF was also suppressed hy vesnarinone, The TNF-induced NF -kappa B activation cascade involving TNF receptor 1-TNF receptor associate d 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-J un N-terminal kinase and mitogen-activated protein kinase kinase, TNF-induc ed cytotoxicity, caspase activation, and lipid peroxidation were also aboli shed by vesnarinone. Overall, our results indicate that vesnarinone inhibit s activation of NF-kappa B and AP-1 and their associated kinases, This may provide a molecular basis for vesnarinone's ability to suppress inflammatio n, immunomodulation, and growth regulation.