Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids.
Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) is the major psychoactive component of marijuana and elicits pharmacological actions via cannabinoid receptors. Anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG) are endogenous ligands for cannabinoid receptors, which because of their structural similarities to arachidonic acid (AA), AEA, and 2-AG could serve as substrates for lipoxygenases and cyclooxygenases (COXs) that metabolize polyunsaturated fatty acids to potent bioactive molecules. In this study, we have compared the effects of Delta(9)-THC, AEA, 2-AG, and another cannabinoid agonist, indomethacin morpholinylamide (IMMA), on lipopolysaccharide (LPS)-induced NO, IL-6, and PGE(2) release from J774 macrophages. Delta(9)-THC, IMMA, and AEA diminish LPS-induced NO and IL-6 production in a concentration-dependent manner. 2-AG inhibits the production of IL-6 but slightly increases iNOS-dependent NO production. Delta(9)-THC and IMMA also inhibit LPS-induced PGE(2) production and COX-2 induction, while AEA and 2-AG have no effects. These discrepant results of 2-AG on iNOS and COX-2 induction might be due to its bioactive metabolites, AA and PGE(2), whose incubation cause the potentiation of both iNOS and COX-2 induction. On the contrary, the AEA metabolite, PGE(2)-ethanolamide, influences neither the LPS-induced NO nor IL-6 production. Taken together, direct cannabinoid receptor activation leads to anti-inflammatory action via inhibition of macrophage function. The endogenous cannabinoid, 2-AG, also serves as a substrate for COX-catalyzing PGE(2) production, which in turn modulates the action of CB2.
Chang
Y H
YH
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Lee
S T
ST
Lin
W W
WW
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology*; D002460:Cell Line; D015232:Dinoprostone / Q000819:agonists / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D015850:Interleukin-6 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000819:agonists / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D001095:Arachidonic Acids; D002186:Cannabinoids; D015777:Eicosanoids; D063388:Endocannabinoids; D005989:Glycerides; D015850:Interleukin-6; D008070:Lipopolysaccharides; D053284:Polyunsaturated Alkamides; D009569:Nitric Oxide; C094503:glyceryl 2-arachidonate; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C078814:anandamide