The synthetic cannabinoid WIN 55,212-2 increases COX-2 expression and PGE2 release in murine brain-derived endothelial cells following Theiler's virus infection
The synthetic cannabinoid WIN 55,212-2 increases COX-2 expression and PGE2 release in murine brain-derived endothelial cells following Theiler's virus infection
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DOI：
10.1016/j.bcp.2006.06.037
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发表时间：
2006-09-28
影响因子：
5.8
通讯作者：
Guaza, Carmen
中科院分区：
文献类型：
--
作者：
Mestre, Leyre;Correa, Fernando;Guaza, Carmen
脑内皮细胞感染是TMEV诱导的脱髓鞘疾病（TMEV-IDD）（多发性硬化症（MS）的一种模型）发病机制中的首要事件之一。事实上，脑内皮细胞中的环氧合酶-2（考克斯-2）表达在MS等中枢神经系统炎症性疾病期间介导了多种作用，并且大麻素改善了TMEV-IDD的进展，这促使我们研究大麻素对TMEV感染或未感染的小鼠脑内皮细胞培养物上的考克斯-2表达的作用。小鼠脑内皮细胞（b.end5）表达大麻素受体CB 1和CB 2。然而，用大麻素激动剂WIN 55，212 -2处理b.end5导致考克斯-2蛋白和PGE（2）释放的上调，其机制独立于这些受体的激活。其他大麻素，如2-花生四烯酸甘油（2-AG）或异常大麻二酚（Abn-CBD）未能影响考克斯-2在我们的条件。TMEV感染小鼠脑内皮细胞培养物诱导考克斯-2表达在8 h显著增加，在感染后20和32 h维持甚至增加。TMEV感染和Win 55，212 -2治疗的组合使考克斯-2表达增加到比单独治疗所观察到的更大的量。2-AG和Abn-CBD对TMEV后考克斯-2表达无影响。WIN 55，212 -2和TMEV感染诱导的考克斯-2合成涉及不同的信号通路。WIN 55，212 -2诱导的考克斯-2上调涉及PI 3 K通路，而TMEV诱导的考克斯-2也需要p38 MAPK激活。考克斯-2的过度表达和随后的PGE 2的增加可能影响血流和/或免疫反应性。(c)2006年爱思唯尔公司All rights reserved.
Brain endothelial cells infection represents one of the first events in the pathogenesis of TMEV-induced demyelination disease (TMEV-IDD), a model of multiple sclerosis (MS). The fact that cyclooxygenase-2 (COX-2) expression in brain endothelium mediates a wide variety of actions during CNS inflammatory diseases such as MS, and that cannabinoids ameliorate the progression of TMEV-IDD, lead us to investigate the role of cannabinoids on COX-2 expression on murine brain endothelial cell cultures subjected or not to TMEV infection. Murine brain endothelial cells (b.end5) express both cannabinoid receptors CB1 and CB2. However, treatment of b.end5 with the cannabinoid agonist WIN 55,212-2 resulted in upregulation COX-2 protein and PGE(2) release by a mechanism independent on activation of these receptors. Other cannabinoids such as 2-arachidonoyl glycerol (2-AG) or the abnormal cannabidiol (Abn-CBD) failed to affect COX-2 in our conditions. TMEV infection of murine brain endothelial cell cultures induced a significant increase of COX-2 expression at 8 h, which was maintained even increased, at 20 and 32 h post-infection. The combination of TMEV infection and Win 55,212-2 treatment increased COX-2 expression to a greater amount than was seen with either treatment alone. 2-AG and Abn-CBD did not modify COX-2 expression after TMEV. COX-2 synthesis involved different signaling pathways when was induced by WIN 55,212-2 and/or by TMEV infection. WIN 55,212-2-induced COX-2 upregulation involves the PI3K pathway, whereas COX-2 induction by TMEV needs p38 MAPK activation too. Overexpression of COX-2 and the subsequent increase of PGE2 could be affecting flow blood and/or immune reactivity. (c) 2006 Elsevier Inc. All rights reserved.