Abstract
The proinflammatory cytokine tumor necrosis factor (TNF)-alpha has been implicated in the attenuation of neutrophil spontaneous apoptosis during sepsis. Antiapoptotic signaling is principally mediated through the p60TNF receptor (p60TNFR). In neutrophils, TNF-alpha is an incomplete secretagogue and requires input from a ligated integrin(s) for neutrophil activation. In adherent neutrophils, TNF-alpha triggers association of both protein kinase C (PKC)-delta and phosphatidylinositol (PI) 3-kinase with the p60TNFR. In this study, a role for PKC-delta and PI 3-kinase in TNF-alpha-mediated antiapoptotic signaling was examined. TNF-alpha inhibited spontaneous apoptosis in fibronectin-adherent neutrophils, and this antiapoptotic signaling was blocked by the PKC-delta inhibitor rottlerin, but not by an inhibitor of Ca(2+)-dependent PKC isotypes, Go-6976. Inhibition of PI 3-kinase by LY-294002 also inhibited TNF-alpha-mediated antiapoptotic signaling. Cycloheximide blocked TNF-alpha-mediated antiapoptotic signaling, suggesting protein synthesis is required. Inhibition of either PKC-delta or PI 3-kinase attenuated TNF-alpha-mediated activation of the antiapoptotic transcription factor NFkappaB. Thus both PKC-delta and PI 3-kinase have essential roles in TNF-alpha-mediated antiapoptotic signaling in adherent neutrophils.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetophenones / administration & dosage
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Acetophenones / pharmacology
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Adult
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Apoptosis / physiology*
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Benzopyrans / administration & dosage
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Benzopyrans / pharmacology
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism
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Cells, Cultured
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Chromones / administration & dosage
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Chromones / pharmacology
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Cycloheximide / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / physiology*
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Morpholines / administration & dosage
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Morpholines / pharmacology
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NF-kappa B / physiology
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Neutrophils / physiology*
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / physiology*
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Protein Kinase C-delta
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Protein Synthesis Inhibitors / pharmacology
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Signal Transduction / physiology*
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factor-alpha / physiology*
Substances
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Acetophenones
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Benzopyrans
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Caspase Inhibitors
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Chromones
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Enzyme Inhibitors
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Isoenzymes
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Morpholines
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Protein Synthesis Inhibitors
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Tumor Necrosis Factor-alpha
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Cycloheximide
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rottlerin
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PRKCD protein, human
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Protein Kinase C
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Protein Kinase C-delta
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CASP3 protein, human
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Caspase 3
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Caspases