TY - JOUR T1 - Prostaglandin E<sub>2</sub> Inhibits the Phospholipase D Pathway Stimulated by Formyl-methionyl-leucyl-phenylalanine in Human Neutrophils. Involvement of EP<sub>2</sub> Receptors and Phosphatidylinositol 3-kinase γ JF - Molecular Pharmacology JO - Mol Pharmacol SP - 293 LP - 301 DO - 10.1124/mol.66.2.293 VL - 66 IS - 2 AU - Chantal Burelout AU - Nathalie Thibault AU - Sylvain Levasseur AU - Sébastien Simard AU - Paul H. Naccache AU - Sylvain G. Bourgoin Y1 - 2004/08/01 UR - http://molpharm.aspetjournals.org/content/66/2/293.abstract N2 - Prostaglandin E2 (PGE2), originally discovered as a pro-inflammatory mediator, also inhibits several chemoattractant-elicited neutrophil functions, including adhesion, secretion of cytotoxic enzymes, production of superoxide anions, and chemotaxis. In this study, we have examined the effects of PGE2 and prostaglandin E (EP) receptor-selective agonists/antagonists on several steps of the formyl-methionyl-leucyl-phenylalanine (fMLP)-induced phospholipase D (PLD) activation pathway in human neutrophils to elucidate the PGE2 inhibitory mechanism. PGE2 and EP2 receptor agonists inhibited the stimulation of the activity of PLD induced by fMLP in a concentration-dependent manner. The fMLP-stimulated translocation to membranes of protein kinase C α, Rho, and Arf GTPases was diminished in the presence of PGE2 or EP2 agonists. Moreover, PGE2 and EP2 agonists decreased the activation of phosphatidylinositol 3-kinase γ (PI3Kγ) and Tec kinases as well as the tyrosine phosphorylation of proteins stimulated by fMLP. These data provide strong evidence that 1) the inhibitory effects of PGE2 on the fMLP-induced PLD activation pathway were mediated via EP2 receptors and that 2) the suppression of PI3Kγ activity was the crucial step in the EP2-mediated inhibition of the fMLP-induced signaling cascade. ER -