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Vesnarinone Suppresses TNF-Induced Activation of NF-B, c-Jun Kinase, and Apoptosis¹

Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

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-B in these responses, we hypothesized that vesnarinone must modulate NF-B activation. We investigated the effect of vesnarinone on NF-B activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-B in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of IB, an inhibitor of NF-B. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-B activation in a variety of cells. NF-B-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-B activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-B-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-B-inducing kinase sites by vesnarinone, thus suppressing NF-B reporter gene expression. Vesnarinone also blocked NF-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-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.

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