A phosphatidylinositol 3-kinase/Akt pathway, activated by tumor necrosis factor or interleukin-1, inhibits apoptosis but does not activate NFkappaB in human endothelial cells.
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) activate the transcription of both anti-apoptotic and pro-inflammatory gene products in human endothelial cells (EC) via NFkappaB. Here we report that both TNF and IL-1 activate the anti-apoptotic protein kinase Akt in growth factor and serum-deprived EC, assessed by Western blotting for phospho-Akt. Phosphorylation of Akt is blocked by LY294002 or wortmannin, inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase). Consistent with these biochemical observations, TNF and IL-1 reduce apoptosis caused by growth factor and serum deprivation, and this action is also blocked by LY294002. Although Akt has been reported to activate NFkappaB, LY294002 does not prevent TNF- or IL-1-induced degradation of IkappaBalpha, beta, or epsilon, transcription of NFkappaB-dependent E-selectin or ICAM-1 promoter-reporter genes, or surface expression of E-selectin or ICAM-1 in human EC. LY294002 potentiates the activation of mitogen-activated protein kinases and stress-activated protein kinases by TNF and IL-1, suggesting Akt inhibits these responses. We conclude that TNF and IL-1 activate a PI 3-kinase/Akt anti-apoptotic pathway and that the anti-apoptotic effects of Akt are independent of NFkappaB. Moreover, the PI 3-kinase/Akt pathway does not play a major role in the pro-inflammatory responses of EC to TNF or IL-1.
Madge
L A
LA
Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
Pober
J S
JS
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human