title: The endocannabinoid 2-arachidonoyl-glycerol activates human neutrophils: critical role of its hydrolysis and de novo leukotriene B4 biosynthesis.
abstract: Although endocannabinoids are important players in nociception and obesity, their roles as immunomodulators remain elusive. The main endocannabinoids described to date, namely 2-arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA), induce an intriguing profile of pro- and anti-inflammatory effects. This could relate to cell-specific cannabinoid receptor expression and/or the action of endocannabinoid-derived metabolites. Importantly, 2-AG and AEA comprise a molecule of arachidonic acid (AA) in their structure and are hydrolyzed rapidly. We postulated the following: 1) the released AA from endocannabinoid hydrolysis would be metabolized into eicosanoids; and 2) these eicosanoids would mediate some of the effects of endocannabinoids. To confirm these hypotheses, experiments were performed in which freshly isolated human neutrophils were treated with endocannabinoids. Unlike AEA, 2-AG stimulated myeloperoxidase release, kinase activation, and calcium mobilization by neutrophils. Although 2-AG did not induce the migration of neutrophils, it induced the release of a migrating activity for neutrophils. 2-AG also rapidly (1 min) induced a robust biosynthesis of leukotrienes, similar to that observed with AA. The effects of 2-AG were not mimicked nor prevented by cannabinoid receptor agonists or antagonists, respectively. Finally, the blockade of either 2-AG hydrolysis, leukotriene (LT) B(4) biosynthesis, or LTB(4) receptor 1 activation prevented all the effects of 2-AG on neutrophil functions. In conclusion, we demonstrated that 2-AG potently activates human neutrophils. This is the consequence of 2-AG hydrolysis, de novo LTB(4) biosynthesis, and an autocrine activation loop involving LTB(4) receptor 1.
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec City, Québec G1V 4G5, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Chouinard
authors.forename: Julie S
authors.initials: JS
authors.lastname: Lefebvre
authors.forename: Pauline
authors.initials: P
authors.lastname: Navarro
authors.forename: Line
authors.initials: L
authors.lastname: Bouchard
authors.forename: Claudine
authors.initials: C
authors.lastname: Ferland
authors.forename: Mélanie
authors.initials: M
authors.lastname: Lalancette-Hébert
authors.forename: David
authors.initials: D
authors.lastname: Marsolais
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
authors.forename: Nicolas
authors.initials: N
authors.lastname: Flamand
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000494:pharmacology / Q000502:physiology; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000097:blood / Q000502:physiology*; D063385:Cannabinoid Receptor Modulators / Q000097:blood / Q000502:physiology*; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D063388:Endocannabinoids; D005989:Glycerides / Q000097:blood / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007975:Leukotriene B4 / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology*; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D007975:Leukotriene B4; D016718:Arachidonic Acid; C094503:glyceryl 2-arachidonate; D001094:Arachidonate 5-Lipoxygenase