Monocyte survival factors induce Akt activation and suppress caspase-3

Am J Respir Cell Mol Biol. 2002 Feb;26(2):224-30. doi: 10.1165/ajrcmb.26.2.4640.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androstadienes / pharmacology
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism*
  • Cell Survival
  • Cells, Cultured
  • Chromones / pharmacology
  • DNA Fragmentation
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Interleukin-1 / pharmacology
  • Interleukin-18 / pharmacology
  • L-Lactate Dehydrogenase / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Monocytes / drug effects
  • Monocytes / enzymology
  • Monocytes / physiology*
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Tumor Necrosis Factor-alpha / pharmacology
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Enzyme Inhibitors
  • Interleukin-1
  • Interleukin-18
  • Lipopolysaccharides
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Tumor Necrosis Factor-alpha
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • L-Lactate Dehydrogenase
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases
  • Wortmannin