Physiological roles of 2-arachidonoylglycerol in the nervous system and the immune system

1.首次观察了2-氨基丁酸在脑内的产生。在本研究中，我们检测了大鼠脑片中2-AG的合成，我们发现去极化的大鼠脑片中2-AG的水平显著增加。在谷氨酸刺激的脑片中也观察到2-AG的产生。我们还发现，用SR141716A处理突触体能显著增强去极化时突触体谷氨酸的释放。这些结果有力地表明，从刺激神经元释放的2-AG可能通过作用于表达的CB1受体而在抑制突触传递中发挥重要的生理作用。主要是在前突触2。接下来研究2-AG在炎症中的生理作用。我们发现2-AG可诱导分化为巨噬细胞样细胞和人外周血单核细胞的HL-60细胞迁移。SR 144528或PTX均能明显抑制2-AG诱导的HL-60细胞迁移，提示这种迁移是通过CB2受体和GI/GO介导的。2-AG对KHYG-1人自然杀伤细胞和人外周血自然杀伤细胞也有诱导迁移作用。我们还发现，在HL-60细胞中加入2-AG可通过CB2受体和GI/GO依赖机制促进IL-8和MCP-1等趋化因子的产生。最后，我们检查了炎症部位2-AG的生成情况。我们发现，小鼠腹腔注射角叉菜胶后，2-AG水平明显升高。这些结果有力地表明，2-AG在炎症反应和免疫反应中具有促进作用而不是抑制作用。

1. The generation of 2-AG in the brain was first examined. In this study, we examined the synthesis of 2-AG in rat brain slices, We found that the level of 2-AG was augmented markedly in depolarized rat brain slices. The generation of 2-AG was also observed in glutamate-stimulated brain slices. We also found that treatment of synaptosomes with SR141716A significantly enhanced the release of glutamate from synaptosomes upon depolarization. These results strongly suggest that 2-AG released from stimulated neurons may have an important physiological role in the attenuation of synaptic transmission by acting on the CB1 receptor expressed. primarily in the presynapse2. Physiological roles of 2-AG in inflammation was next examined. We found that 2-AG induces the migration of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes. The 2-AG-induced migration of HL-60 cells was markedly reduced when the cells were pretreated with either SR 144528 or PTX, suggesting that the migration was mediated through the CB2 receptor and Gi/Go. The 2-AG-induced migration was also observed with KHYG-1 human natural killer cells and human peripheral blood natural killer cells. We also found that the addition of 2-AG to HL-60 cells enhanced the production of chemokines such as IL-8 and MCP-1 through a CB2 receptor-and Gi/Go-dependent mechanism. Finally, we examined the generation of 2-AG at the site of inflammation. We found that the level of 2-AG was markedly elevated in mouse peritoneal cavity injected with carrageenan. These results strongly suggest that 2-AG has a stimulative rather than suppressive role during inflammatory reactions and immune 1 responses