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Prostaglandin E2 signals monocyte/macrophage survival to peroxynitrite via protein kinase A converging in bad phosphorylation with the protein kinase C alpha-dependent pathway driven by 5-hydroxyeicosatetraenoic acid.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2008 Oct 15; Vol. 181 (8), pp. 5637-45. - Publication Year :
- 2008
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Abstract
- Monocytes/macrophages committed to death by peroxynitrite nevertheless survive with a signaling response promoting Bad phosphorylation, as well as its cytosolic localization, via upstream activation of cytosolic phospholipase A(2), 5-lipoxygenase, and protein kinase C alpha. We now report evidence for an alternative mechanism converging in Bad phosphorylation when the expression/activity of the above enzymes are suppressed. Under these conditions, also associated with peroxynitrite-dependent severe inhibition of Akt, an additional Bad kinase, Bad dephosphorylation promoted its accumulation in the mitochondria and a prompt lethal response. PGE(2) prevented toxicity via EP(2) receptor-mediated protein kinase A-dependent Bad phosphorylation. This notion was established in U937 cells by the following criteria: 1) there was a strong correlation between survival and cAMP accumulation, both in the absence and presence of phosphodiesterase inhibitors; 2) direct activation of adenylyl cyclase afforded cytoprotection; and 3) PGE(2) promoted loss of mitochondrial Bad and cytoprotection, mimicked by EP(2) receptor agonists, and prevented by EP(2) receptor antagonists or protein kinase A inhibitors. Finally, selected experiments performed in human monocytes/macrophages and in rat peritoneal macrophages indicated that the above cytoprotective pathway is a general response of cells belonging to the monocyte/macrophage lineage to both exogenous and endogenous peroxynitrite. The notion that two different pathways mediated by downstream products of arachidonic acid metabolism converge in Bad phosphorylation emphasizes the relevance of this strategy for the regulation of macrophage survival to peroxynitrite at the inflammatory sites.
- Subjects :
- Adenylyl Cyclase Inhibitors
Adenylyl Cyclases immunology
Animals
Cell Death drug effects
Cell Death immunology
Cell Survival drug effects
Cell Survival immunology
Cyclic AMP immunology
Cyclic AMP metabolism
Cyclic AMP-Dependent Protein Kinases antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinases metabolism
Dinoprostone metabolism
Dinoprostone pharmacology
Enzyme Activation drug effects
Enzyme Activation immunology
Humans
Hydroxyeicosatetraenoic Acids immunology
Hydroxyeicosatetraenoic Acids metabolism
Inflammation enzymology
Inflammation immunology
Macrophages, Peritoneal enzymology
Mitochondrial Proteins metabolism
Monocytes enzymology
Peroxynitrous Acid metabolism
Phospholipase A2 Inhibitors
Phospholipases A2 immunology
Phospholipases A2 metabolism
Phosphorylation drug effects
Protein Kinase C-alpha antagonists & inhibitors
Protein Kinase C-alpha metabolism
Proto-Oncogene Proteins c-akt immunology
Proto-Oncogene Proteins c-akt metabolism
Rats
Rats, Sprague-Dawley
Receptors, Prostaglandin E immunology
Receptors, Prostaglandin E metabolism
Receptors, Prostaglandin E, EP2 Subtype
Signal Transduction drug effects
U937 Cells
bcl-Associated Death Protein metabolism
Cyclic AMP-Dependent Protein Kinases immunology
Dinoprostone immunology
Macrophages, Peritoneal immunology
Mitochondrial Proteins immunology
Monocytes immunology
Peroxynitrous Acid immunology
Protein Kinase C-alpha immunology
Signal Transduction immunology
bcl-Associated Death Protein immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 181
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 18832722
- Full Text :
- https://doi.org/10.4049/jimmunol.181.8.5637