Wortmannin inhibits activation of nuclear transcription factors NF-kappaB and activated protein-1 induced by lipopolysaccharide and phorbol ester

FEBS Lett. 2000 May 4;473(1):113-8. doi: 10.1016/s0014-5793(00)01501-5.

Abstract

Whether all inflammatory agents activate nuclear transcription factors NF-kappaB and activated protein-1 (AP-1) through the same mechanism is not known. We examined the effect of the phosphatidylinositol-3-kinase (PI-3K) inhibitor wortmannin on the activation of NF-kappaB and AP-1 by different inflammatory agents. Wortmannin blocked NF-kappaB and AP-1 activation by lipopolysaccharide and phorbol ester but had minimal effect on activation by hydrogen peroxide, ceramide, okadaic acid and tumor necrosis factor. Inhibition of NF-kappaB correlated with abrogation of the degradation of IkappaBalpha and of NF-kappaB-dependent reporter gene transcription. Thus, the mechanism of NF-kappaB and AP-1 activation by lipopolysaccharide and phorbol ester involves PI-3K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Androstadienes / pharmacology*
  • Ceramides / antagonists & inhibitors
  • Ceramides / pharmacology
  • DNA Probes / genetics
  • DNA Probes / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Genes, Reporter / genetics
  • Humans
  • Hydrogen Peroxide / pharmacology
  • I-kappa B Proteins*
  • Lipopolysaccharides / antagonists & inhibitors*
  • Lipopolysaccharides / pharmacology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Okadaic Acid / pharmacology
  • Organ Specificity
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Signal Transduction / drug effects
  • Tetradecanoylphorbol Acetate / antagonists & inhibitors*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Time Factors
  • Transcription Factor AP-1 / antagonists & inhibitors
  • Transcription Factor AP-1 / metabolism*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology
  • Wortmannin

Substances

  • Androstadienes
  • Ceramides
  • DNA Probes
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • NFKBIA protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Okadaic Acid
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Hydrogen Peroxide
  • Tetradecanoylphorbol Acetate
  • Wortmannin