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

Abstract

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.

• Authors: S K Manna, B B Aggarwal
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 164 Issue 11 Pg. 5815-25 (Jun 01 2000) ISSN: 0022-1767 [Print] United States
• PMID: 10820260 (Publication Type: Journal Article)

Chemical References

• Ceramides
• DNA-Binding Proteins
• Enzyme Inhibitors
• I-kappa B Proteins
• Immunosuppressive Agents
• Lipopolysaccharides
• NF-kappa B
• NF-kappa B p50 Subunit
• NFKBIA protein, human
• Pyrazines
• Quinolines
• Transcription Factor AP-1
• Transcription Factor RelA
• Tumor Necrosis Factor-alpha
• NF-KappaB Inhibitor alpha
• Okadaic Acid
• vesnarinone
• DNA
• Hydrogen Peroxide
• Chloramphenicol O-Acetyltransferase
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase Kinases
• Tetradecanoylphorbol Acetate
• Uridine

Topics

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