Roles of endogenous cannabinoid receptor ligands in acute inflammation and allergic

内源性大麻素受体配体在急性炎症和过敏中的作用

• 批准号: 17590072
• 负责人: KISHIMOTO Seishi
• 金额: $ 2.37万
• 依托单位: Teikyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590072/
• 关键词: cannabinoid; CB2 receptor; 2-arachidonoylglycerol; inflammation; allergy; eosinophil; natural killer; monocyte; macrophage; allergic inflammation; dermatitis; chemotaxis; innate immunity; natural killer cell

In this study, we investigated possible pathophysiological roles of CB2 cannabinoid receptor and its endogenous ligand, 2-arachidonoylglycerol (2-AG), in acute inflammation and allergic inflammation.1. 2-AG was found to enhance the adhesion of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes to fibronectin and VCAM-1. The CB2 receptor, Gi/o and PI 3-kinase were shown to be involved in 2-AG-augmented cell adhesion.2. We found that the amount of 2-AG was markedly augmented in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in 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. Interestingly, the application of 2-AG to the mouse ear evoked swelling. On the other hand, we demonstrated that WIN55212-2, a synthetic cannabinoid receptor agonist, suppressed mouse ear swelling induced by topical application … More TPA. It was suggested that the anti-inflammatory activity of WIN55212-2 is attribute to interference with the actions of the endogenous ligand, 2-AG.3. 2-AG and 2-AG ether, an ether linked nonhydrolysable analog of 2-AG, was shown to induce the migration of human peripheral blood eosinophils.4. Augmentation of the amount of 2-AG was observed with oxazolone-induced allergic inflammation of mouse ear. Oxazolone-induced ear swelling was inhibited by treatment with SR144528 of the mice. Furthermore, treatment with SR144528 attenuated the recruitment of eosinophils and ear swelling in chronic contact dermatitis induced by repeated challenge with oxazolone.5. We also found that 2-AG induces the migration of human natural killer cells. In contrast to 2-AG, anandamide and Δ^9-tetrahydrocannabinol failed to induce the migration.These results suggest that the CB2 receptor and 2-AG play crucial simulative roles during the course of inflammatory reactions in acute inflammation and allergic inflammation. Less

在这项研究中，我们探讨了CB2大麻素受体及其内源性配体2-花生四烯醇甘油（2-AG）在急性炎症和变应性炎症中的可能病理生理作用。发现2-AG能增强HL-60细胞分化为巨噬细胞样细胞和人外周血单核细胞对纤维连接蛋白和VCAM-1的粘附。CB2受体、Gi/o和PI 3-激酶被证明参与了2- ag增强的细胞粘附。我们发现，12- o -十四烷醇-13-乙酸酯（TPA）诱导的小鼠耳急性炎症中2-AG的数量明显增加。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。有趣的是，将2-AG应用于小鼠耳会引起肿胀。另一方面，我们证明了WIN55212-2，一种合成大麻素受体激动剂，可以抑制外用引起的小鼠耳部肿胀。提示WIN55212-2的抗炎活性与内源性配体2- ag的干扰有关。2-AG和2-AG醚（一种与2-AG相连的不可水解类似物）可诱导人外周血嗜酸性粒细胞迁移。恶唑酮致小鼠耳廓变应性炎症使2-AG含量增加。SR144528可抑制恶唑酮所致小鼠耳肿胀。此外，SR144528治疗可以减少嗜酸性粒细胞的募集和恶唑酮反复刺激引起的慢性接触性皮炎的耳部肿胀。我们还发现2-AG诱导人类自然杀伤细胞的迁移。与2-AG相比，anandamide和Δ^9-四氢大麻酚未能诱导迁移。这些结果表明，CB2受体和2-AG在急性炎症和变应性炎症的炎症反应过程中起着重要的模拟作用。少