Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation

J Immunol. 2000 Jun 15;164(12):6509-19. doi: 10.4049/jimmunol.164.12.6509.

Abstract

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, fruits, and root extracts of the weed Polygonum cuspidatum, exhibits anti-inflammatory, cell growth-modulatory, and anticarcinogenic effects. How this chemical produces these effects is not known, but it may work by suppressing NF-kappaB, a nuclear transcription factor that regulates the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this study, we investigated the effect of resveratrol on NF-kappaB activation induced by various inflammatory agents. Resveratrol blocked TNF-induced activation of NF-kappaB in a dose- and time-dependent manner. Resveratrol also suppressed TNF-induced phosphorylation and nuclear translocation of the p65 subunit of NF-kappaB, and NF-kappaB-dependent reporter gene transcription. Suppression of TNF-induced NF-kappaB activation by resveratrol was not restricted to myeloid cells (U-937); it was also observed in lymphoid (Jurkat) and epithelial (HeLa and H4) cells. Resveratrol also blocked NF-kappaB activation induced by PMA, LPS, H2O2, okadaic acid, and ceramide. The suppression of NF-kappaB coincided with suppression of AP-1. Resveratrol also inhibited the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase activation. Both reactive oxygen intermediate generation and lipid peroxidation induced by TNF were suppressed by resveratrol. Resveratrol's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappaB and AP-1 and the associated kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Biological Transport / drug effects
  • Caspase Inhibitors
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Ceramides / antagonists & inhibitors
  • Ceramides / pharmacology
  • Cytotoxicity, Immunologic / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Genes, Reporter / drug effects
  • Humans
  • Hydrogen Peroxide / antagonists & inhibitors
  • Hydrogen Peroxide / pharmacology
  • I-kappa B Proteins*
  • Immunosuppressive Agents / pharmacology*
  • JNK Mitogen-Activated Protein Kinases
  • Lipid Peroxidation / drug effects*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Kinase Kinase 1*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • NF-kappa B p50 Subunit
  • Okadaic Acid / antagonists & inhibitors
  • Okadaic Acid / pharmacology
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Reactive Oxygen Species / physiology*
  • Resveratrol
  • Stilbenes / pharmacology*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor AP-1 / antagonists & inhibitors*
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Caspase Inhibitors
  • Ceramides
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • Immunosuppressive Agents
  • Lipopolysaccharides
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • NFKBIA protein, human
  • Reactive Oxygen Species
  • Stilbenes
  • Transcription Factor AP-1
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Okadaic Acid
  • Hydrogen Peroxide
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Tetradecanoylphorbol Acetate
  • Resveratrol