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

在这项研究中，我们首先研究了CB 2受体和2-AG在局部应用TPA诱导的小鼠耳急性炎症中可能的病理生理作用。我们发现，2-AG的量显着增加，在发炎的小鼠耳。重要的是，TPA诱导的耳肿胀被CB 2受体拮抗剂SR 144528阻断，表明CB 2受体参与肿胀。SR 144528的应用还减少TPA诱导的小鼠耳中LTB_4的产生和中性粒细胞的浸润。在小鼠耳中观察到恶唑酮诱导的过敏性炎症的类似结果。有趣的是，2-AG应用于小鼠耳诱发肿胀，其通过SR 144528处理消除。提示一氧化氮参与了2-AG诱导的小鼠耳肿胀。这些结果表明，CB_2受体和2-AG在炎症反应过程中起着关键的刺激作用。我们接下来研究了2-AG对分化为巨噬细胞样细胞的HL-60细胞粘附的影响。我们发现，2-AG增强分化的HL-60细胞与纤连蛋白和VCAM-1的粘附。CB 2受体、Gi/Go和PI 3-激酶参与2-AG诱导的细胞粘附增强。2-AG还能促进人单核细胞白血病U937细胞与外周血单核细胞的粘附。这些结果强烈表明，2-AG通过诱导几种类型的炎性细胞和免疫活性细胞中的细胞外基质蛋白和粘附分子的牢固粘附，在炎症反应和免疫应答中起着重要作用。

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.