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.
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.
Tommasini
Ilaria
I
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino Carlo Bo, Urbino, Italy.
Cerioni
Liana
L
Palomba
Letizia
L
Cantoni
Orazio
O
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000276:immunology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology*; D024101:Mitochondrial Proteins / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000276:immunology*; D030421:Peroxynitrous Acid / Q000276:immunology* / Q000378:metabolism; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000276:immunology / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D020298:U937 Cells; D051025:bcl-Associated Death Protein / Q000276:immunology* / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; C494819:BAD protein, human; C494821:Bad protein, rat; D006893:Hydroxyeicosatetraenoic Acids; D024101:Mitochondrial Proteins; C545644:PTGER2 protein, human; D064801:Phospholipase A2 Inhibitors; C545646:Ptger2 protein, rat; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051025:bcl-Associated Death Protein; D030421:Peroxynitrous Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D051571:Protein Kinase C-alpha; D054467:Phospholipases A2; D000262:Adenylyl Cyclases; D015232:Dinoprostone