Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis.
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.
Manna
S K
SK
Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Aggarwal
B B
BB
D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport / Q000187:drug effects; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019450:Genes, MDR / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D019319:Okadaic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011719:Pyrazines; D011804:Quinolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020298:U937 Cells; D014529:Uridine / Q000494:pharmacology
D002518:Ceramides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D011719:Pyrazines; D011804:Quinolines; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D019319:Okadaic Acid; C041667:vesnarinone; D004247:DNA; D006861:Hydrogen Peroxide; D015500:Chloramphenicol O-Acetyltransferase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate; D014529:Uridine