Abstract
Δ^9^‐Tetrahydrocannabinol (Δ^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 Δ^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. Δ^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. Δ^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. J. Cell. Biochem. 81: 715–723, 2001. © 2001 Wiley‐Liss, Inc.