Effects of cannabinoids on LPS‐stimulated inflammatory mediator release from macrophages: Involvement of eicosanoids

Abstract

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.

Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6

“…However, it also is a known substrate for the COX and lipoxygenase enzymes (19,21,38). Some of the effects of 2-AG have been shown to be mediated by some of its metabolites, such as arachidonic acid and its PG derivatives, or through the action of 2-AG on the PPARs (10,19,(39)(40)(41). Although it is known that PG-Gs constitute COX-derived 2-AG metabolites, their effects are not well documented.…”

“…The endocannabinoid 2-arachidonoylglycerol (2-AG) is involved in various (patho)physiological processes and exerts numerous beneficial actions (ranging from pain modulation to reduction of anxiety) (5)(6)(7)(8)(9)(10)(11). The activity of this bioactive lipid depends on its endogenous levels, tightly controlled by the 2-AG hydrolyzing enzymes (12).…”

Involvement of the Cannabinoid CB2 Receptor and Its Endogenous Ligand 2-Arachidonoylglycerol in Oxazolone-Induced Contact Dermatitis in Mice

“…These results strongly suggest that the CB2 receptor and 2-AG play essential roles in the stimulation of various types of inflammatory reactions and immune responses. In contrast, several investigators reported that the CB2 receptor and 2-AG may play suppressive roles in inflammatory reactions and immune responses (31)(32)(33)(34), although the suppressive effects of exogenous 2-AG are assumed to be due to arachidonic acid metabolites derived from 2-AG rather than 2-AG itself in some cases.…”

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

“…Indeed, cannabinoids such as anandamide, noladin ether, and arachidonoylcyclopropylamide (ACPA) induce wound-closure in human colonic epithelial cell lines, suggesting that delayed wound healing, a feature of IBD lesions, might be reversed by cannabinoids [34]. Additionally, in vitro studies suggest roles for both cannabinoid receptors in modulating inflammatory processes, including suppression of the activation of macrophages and mast cells, secretion of proinflammatory cytokines, and modulation of T helper lymphocytes by reducing the activated T cell population, inducing their apoptosis, and inhibiting their proliferation [33,[35][36][37][38][39][40].…”

“…This results in a change from immune tolerance to immune activation [41][42][43]. Pro-inflammatory cytokines are known to alter the barrier function [39,40], thus forming a vicious circle where increased inflammation leads to a further increase in intestinal permeability. In monolayers of Caco-2 cells, a model of the intestinal epithelial barrier, application of EDTA, pro-inflammatory cytokines, or LPS increases permeability as measured by a decrease in trans-epithelial…”