title: Inhibition of platelet-activating factor biosynthesis by adenosine and histamine in human neutrophils: involvement of cPLA2alpha and reversal by lyso-PAF.
abstract: Leukotrienes (LT) and platelet-activating factor (PAF) are important lipid mediators of inflammation. We and others reported previously that autacoids such as adenosine, histamine, prostaglandin E2, and beta-adrenergic agents inhibit LT biosynthesis in activated human polymorphonuclear leukocytes (PMN). In this study, we demonstrate that CGS-21680 (a selective agonist of the adenosine A2A receptor) and histamine also potently inhibit PAF biosynthesis in agonist [formyl Met-Leu-Phe (fMLP)]- and thapsigargin-activated human PMN. The observed inhibitions of PAF biosynthesis were reversed effectively by exogenous 1-O-alkyl-lyso-sn-glyceryl-3-phosphocholine (lyso-PAF), suggesting that these effects of CGS-21680 and histamine implicate the blockade of cytosolic phospholipase A2alpha (cPLA2alpha) activity and lyso-PAF release and that the acetyl-coenzyme A/lyso-PAF acetyl transferase is not inhibited by the autacoids. Accordingly, the cPLA2alpha inhibitor pyrrophenone completely blocked PAF formation, and lyso-PAF similarly prevented this effect of pyrrophenone. The inhibitory effects of CGS-21680 and histamine on PAF biosynthesis were prevented by the protein kinase A inhibitor H-89, supporting roles for the Gs -coupled receptors A2A and H2, respectively, and cyclic adenosine monophosphate in the inhibitory mechanism. The fMLP-induced phosphorylations of p38 and extracellular signal-regulated kinase 1/2 were not altered significantly by the CGS-21680, indicating that inhibition of these kinases is not involved in the inhibitory effect of the adenosine A2A receptor ligand on LT and PAF biosynthesis. These data further emphasize the multiple and potent inhibitory effects of adenosine and histamine on leukocyte functions, in particular, on the biosynthesis of two classes of important lipid mediators and their putative regulatory roles in immune processes in health and diseases.
authors.affiliation: Centre de Recherche du Rhumatologie et Immunologie, Centre de Recherche du CHUQ (CHUL), Faculté de Médecine, Université Laval, Québec, Canada G1V 4G2.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Flamand
authors.forename: Julie
authors.initials: J
authors.lastname: Lefebvre
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lapointe
authors.forename: Serge
authors.initials: S
authors.lastname: Picard
authors.forename: Lise
authors.initials: L
authors.lastname: Lemieux
authors.forename: Sylvain G
authors.initials: SG
authors.lastname: Bourgoin
authors.forename: Pierre
authors.initials: P
authors.lastname: Borgeat
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000959:Antihypertensive Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054513:Group IV Phospholipases A2; D006632:Histamine / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008563:Membrane Lipids / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000187:drug effects / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D015289:Leukotrienes; D008563:Membrane Lipids; C029271:O-deacetyl platelet activating factor; D010627:Phenethylamines; D010743:Phospholipids; D010972:Platelet Activating Factor; D011759:Pyrrolidines; D043705:Receptor, Adenosine A2A; D044042:Receptors, Formyl Peptide; D011970:Receptors, Histamine H2; C455981:pyrrophenone; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D006632:Histamine; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D000241:Adenosine