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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-Dependent Pathway Driven by 5-Hydroxyeicosatetraenoic Acid¹

Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo", Urbino, Italy

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 A₂, 5-lipoxygenase, and protein kinase C. 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. PGE₂ prevented toxicity via EP₂ 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) PGE₂ promoted loss of mitochondrial Bad and cytoprotection, mimicked by EP₂ receptor agonists, and prevented by EP₂ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (to O.C.).

² I.T. and L.C. contributed equally to the work described in this paper.

³ Address correspondence and reprint requests to Dr. Orazio Cantoni, Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo", via Santa Chiara 27, 61029 Urbino (PU), Italy. E-mail address: orazio.cantoni{at}uniurb.it

⁴ Abbreviations used in this paper: ARA, arachidonic acid; AACOCF₃, arachidonyl trifluoromethyl ketone; AS-ON, antisense oligonucleotide; cPLA₂, cytosolic phospholipase A₂; FLAP, 5-LO-activating protein; 5-HETE, 5-hydroxyeicosatetraenoic acid; IBMX, 3-isobutyl-1-methylxanthine; L-NAME, N^G-nitro-L-arginine methyl ester; 5-LO, 5-lipoxygenase; MPT, mitochondrial permeability transition; NS-ON, nonsense oligonucleotide; ON, oligonucleotide; PKA, protein kinase A; PKC, protein kinase C.

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