title: A beneficial aspect of a CB1 cannabinoid receptor antagonist: SR141716A is a potent inhibitor of macrophage infection by the intracellular pathogen Brucella suis.
abstract: The psychoactive component of marijuana, delta9-tetrahydrocannabinol (THC) suppresses different functions of immunocytes, including the antimicrobicidal activity of macrophages. The triggering of cannabinoid receptors of CB1 and CB2 subtypes present on leukocytes may account for these effects. We investigated the influence of specific CB1 or CB2 receptor antagonists (SR141716A and SR144528, respectively) and nonselective CB1/CB2 cannabinoid receptor agonists (CP55,940 or WIN 55212-2) on macrophage infection by Brucella suis, an intracellular gram-negative bacteria. None of the compounds tested affected bacterial phagocytosis. By contrast, the intracellular multiplication of Brucella was dose-dependently inhibited in cells treated with 10-500 nM SR141716A and 1 microM SR141716A-induced cells exerted a potent microbicidal effect against the bacteria. SR144528, CP55,940, or WIN 55212-2 did not affect (or slightly potentiated) the growth of phagocytized bacteria. However, CP55,940 or WIN 55212-2 reversed the SR141716A-mediated effect, which strongly suggested an involvement of macrophage CB1 receptors in the phenomenon. SR141716A was able to pre-activate macrophages and to trigger an activation signal that inhibited Brucella development. The participation of endogenous cannabinoid ligand(s) in Brucella infection was discussed. Finally, our data show that SR141716A up-regulates the antimicrobial properties of macrophages in vitro and might be a pharmaceutical compound useful for counteracting the development of intramacrophagic gram-negative bacteria.
authors.affiliation: INSERM U431, IFR Eugène Bataillon, Université de Montpellier-II, France. U431@crit.univ-montp2.fr
authors.forename: A
authors.initials: A
authors.lastname: Gross
authors.forename: A
authors.initials: A
authors.lastname: Terraza
authors.forename: J
authors.initials: J
authors.lastname: Marchant
authors.forename: M
authors.initials: M
authors.lastname: Bouaboula
authors.forename: S
authors.initials: S
authors.lastname: Ouahrani-Bettache
authors.forename: J P
authors.initials: JP
authors.lastname: Liautard
authors.forename: P
authors.initials: P
authors.lastname: Casellas
authors.forename: J
authors.initials: J
authors.lastname: Dornand
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis; D048588:Benzoxazines; D002002:Brucella / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology*; D002117:Calcitriol / Q000494:pharmacology; D001892:Camphanes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077285:Rimonabant
chemical_list: D000900:Anti-Bacterial Agents; D015703:Antigens, CD; D048588:Benzoxazines; D001892:Camphanes; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C110630:SR 144528; D018799:Intercellular Adhesion Molecule-1; D005576:Colforsin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP; D002117:Calcitriol; D000077285:Rimonabant