Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1β-stimulated human astrocytes
Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1β-stimulated human astrocytes
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DOI：
10.1002/glia.20108
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发表时间：
2005-01-15
期刊：
影响因子：
6.2
通讯作者：
Peterson, PK
中科院分区：
文献类型：
--
作者：
Sheng, WS;Hu, SX;Peterson, PK
活化的神经胶质细胞与脑的许多感染性和炎性疾病的神经发病机制有关。已经提出许多炎症介质在神经胶质细胞相关的脑损伤中起作用：例如自由基如一氧化氮（NO）、细胞因子和趋化因子。我们的实验室一直对精神活性药物及其衍生物对这些介质产生的影响感兴趣。大麻素已被证明具有免疫调节以及精神活性特性。我们以前已经证明白细胞介素（W-1 β）刺激的人星形胶质细胞，而不是小胶质细胞，产生NO。我们研究了合成大麻素WIN 55，212-2对IL-1 β激活的人胎儿星形胶质细胞产生几种关键炎症介质的影响。在人星形胶质细胞上检测到大麻素受体CB 1和CB 2的表达。WIN55.212-2（10（-5）M）有效抑制诱导型NO合酶（iNOS）和IL-1 β刺激的星形胶质细胞产生的相应NO。CB 1和CB 2受体特异性拮抗剂SR 141716 A和SR 144528分别部分阻断了这种抑制作用。此外，用WIN 55，212-2处理星形胶质细胞以浓度依赖性方式下调IL-1 β诱导的肿瘤坏死因子（TNF）-α释放。用WIN 55，212-2处理也抑制IL-1 β激活的星形胶质细胞产生趋化因子CXCL 10，CCL 2和CCL 5。这些发现表明，WIN55.212-2抑制IL-1 β刺激的人星形胶质细胞产生炎症介质，并表明类似的药物可能具有治疗脑炎症的潜力。(C)2004年威利-利斯。Inc.
Activated glial cells have been implicated in the neuropathogenesis of many infectious and inflammatory diseases of the brain. A number of inflammatory-mediators have been proposed to play a role in glial cell-related brain damage: e.g. free radicals such as nitric oxide (NO), cytokines, and chemokines. Our laboratory has been interested in the effect of psychoactive drugs and their derivatives on the production of these mediators. Cannabinoids have been shown to possess immunomodulatory as well as psychoactive properties. We previously have shown that interleukin (W-1beta-Stimulated human astrocytes, but not microglia, produce NO. In this study. we investigated the effects of the synthetic cannabinoid WIN55,212-2 on the production of Several key inflammatory mediators by human fetal astrocytes activated by IL-1beta. Expression of the cannabinoid receptors CB1 and CB2 was detected on human astrocyteS. WIN55.212-2 (10(-5) M) potently inhibited inducible NO synthase (iNOS) and corresponding ,NO production by IL-1beta-stimulated astrocytes. The CB1 and CB2 receptor-specific antagonists SR141716A and SR144528, respectively, partially blocked this suppressive effect. In addition, treatment of astrocytes with WIN55,212-2 downregulated in a concentration-dependent manner IL-1beta-induced tumor necrosis factor (TNF)-alpha release. Treatment with WIN55,212-2 also inhibited production of the chemokines CXCL10, CCL2 and CCL5 by IL-1beta-activated astrocytes. These findings indicate that WIN55.212-2 inhibits the production of inflammatory mediators by IL-1beta-stimulated human astrocyteS and suggest that comparable agents may have therapeutic potential for the management of brain inflammation. (C) 2004 Wiley-Liss. Inc.