Physiological roles of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand

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In this study, we first investigated possible pathophysiological roles of the CB2 receptor and 2-AG in acute inflammation in mouse ear induced by the topical application of TPA. We found that the amount of 2-AG was markedly augmented in inflamed mouse ear. Importantly, TPA-induced ear swelling was blocked by treatment with SR144528, a CB2 receptor antagonist, suggesting that the CB2 receptor is involved in the swelling. The application of SR144528 also reduced the TPA-induced production of LTB_4 and the infiltration of neutrophils in the mouse ear. Similar results observed with oxazolone-induced allergic inflammation in mouse ear. Interestingly, the application of 2-AG to the mouse ear evoked swelling, which was abolished by treatment with SR144528. Nitric oxide was suggested to be involved in the ear swelling induced by 2-AG. These results suggest that the CB2 receptor and 2-AG play crucial stimulative roles during the course of inflammatory reactions.We next examined the effect of 2-AG on the adhesion of HL-60 cells differentiated into macrophage-like cells. We found that 2-AG enhanced the adhesion of differentiated HL-60 cells to fibronectin and VCAM-1. The CB2 receptor, Gi/Go and PI 3-kinase were shown to be involved in 2-AG-induced augmented cell adhesion. 2-AG also enhanced the adhesion of human monocytic leukemia U937 cells and peripheral blood monocytes. These results strongly suggest that 2-AG plays some essential role in inflammatory reactions and immune responses by inducing robust adhesion to extracellular matrix proteins and adhesion molecules in several types of inflammatory cells and immune-competent cells.