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

在本研究中，我们首先探讨了CB2受体和2-AG在局部应用TPA诱导的小鼠耳部急性炎症中的可能病理生理作用。我们发现，2-AG的数量在炎症小鼠耳中明显增加。重要的是，用CB2受体拮抗剂SR144528治疗可以阻断tpa诱导的耳部肿胀，这表明CB2受体参与了肿胀。SR144528的应用也减少了tpa诱导的小鼠耳内LTB_4的产生和中性粒细胞的浸润。在恶唑酮引起的小鼠耳部变应性炎症中观察到类似的结果。有趣的是，将2-AG应用于小鼠耳部会引起肿胀，而SR144528可以消除这种肿胀。提示一氧化氮参与了2-AG引起的耳部肿胀。这些结果表明，CB2受体和2-AG在炎症反应过程中起着重要的刺激作用。接下来，我们检测了2-AG对HL-60细胞分化为巨噬细胞样细胞粘附的影响。我们发现2-AG增强分化的HL-60细胞对纤维连接蛋白和VCAM-1的粘附。CB2受体、Gi/Go和PI 3-激酶参与了2- ag诱导的细胞粘附增强。2-AG对人单核细胞白血病U937细胞和外周血单核细胞的粘附也有增强作用。这些结果强烈提示，2-AG通过诱导多种类型的炎症细胞和免疫能力细胞对细胞外基质蛋白和粘附分子的粘附，在炎症反应和免疫反应中发挥重要作用。

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.