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Inhibition of platelet‐activating factor biosynthesis by adenosine and histamine in human neutrophils: involvement of cPLA 2 α and reversal by lyso‐PAF
Author(s) -
Flamand Nicolas,
Lefebvre Julie,
Lapointe Gabriel,
Picard Serge,
Lemieux Lise,
Bourgoin Sylvain G.,
Borgeat Pierre
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1005614
Subject(s) - platelet activating factor , biology , histamine , adenosine , platelet , biosynthesis , medicine , endocrinology , immunology , pharmacology , biochemistry , enzyme
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 E 2 , and β‐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 A 2A 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 A 2 α (cPLA 2 α) activity and lyso‐PAF release and that the acetyl‐coenzyme A/lyso‐PAF acetyl transferase is not inhibited by the autacoids. Accordingly, the cPLA 2 α 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 G s ‐coupled receptors A 2A and H 2 , 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 A 2A 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.