Wortmannin inhibits activation of nuclear transcription factors NF-kappaB and activated protein-1 induced by lipopolysaccharide and phorbol ester.
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.
Manna
S K
SK
Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, P.O. Box 143, Houston, TX 77030, USA.
Aggarwal
B B
BB
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology*; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015342:DNA Probes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000077191:Wortmannin
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000730:Androstadienes; D002518:Ceramides; D015342:DNA Probes; D004268:DNA-Binding Proteins; D006861:Hydrogen Peroxide; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D019319:Okadaic Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; C000606204:NFKBIA protein, human