title: Monocyte survival factors induce Akt activation and suppress caspase-3.
abstract: A number of inflammatory cytokines and growth factors promote monocyte survival; however, the biochemical events stimulated by these factors are poorly defined. We previously showed that the monocyte survival factor macrophage colony-stimulating factor (M-CSF) activated monocyte survival through a PI 3-kinase-dependent pathway resulting in the phosphorylation of Akt and the suppression of the activation of caspase-3. Because other cytokines and bacterial cell wall products also induce monocyte survival, we hypothesized that these factors may also suppress caspase-3 and caspase-9 activation and activate Akt in human monocytes. To test this hypothesis, we found that interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), granulocyte macrophage-colony-stimulating factor (GM-CSF), and IL-18 appeared to suppress DNA fragmentation, caspase-9, and caspase-3 activation in human monocytes. Moreover, these stimuli appeared to induce the serine and threonine phosphorylation of Akt, which was reduced by the PI 3-kinase inhibitor LY294002. Using in vitro kinase assays, M-CSF appeared to induce more Akt activity than did the other survival factors. Treatment of monocytes with either LY294002 or wortmannin resulted in caspase-3 activation in the presence of these survival factors. These results suggest that monocyte survival factors may suppress DNA fragmentation, caspase-9, and caspase-3 activation in a PI 3-kinase-dependent manner, perhaps through the activation of Akt.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, The Ohio State University College of Medicine and Public Health, 1654 Upham Drive, Columbus, OH 43210, USA.
authors.forename: Anuj
authors.initials: A
authors.lastname: Goyal
authors.forename: Yijie
authors.initials: Y
authors.lastname: Wang
authors.forename: Mandy M
authors.initials: MM
authors.lastname: Graham
authors.forename: Andrea I
authors.initials: AI
authors.lastname: Doseff
authors.forename: Nitin Y
authors.initials: NY
authors.lastname: Bhatt
authors.forename: Clay B
authors.initials: CB
authors.lastname: Marsh
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D053938:DNA Fragmentation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D002867:Chromones; D004791:Enzyme Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007375:Interleukin-1; D020382:Interleukin-18; D007770:L-Lactate Dehydrogenase; D008070:Lipopolysaccharides; D016173:Macrophage Colony-Stimulating Factor; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C505407:CASP3 protein, human; C506433:CASP9 protein, human