Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes
Induction of COX-2 Enzyme and Down-regulation of COX-1 Expression by Lipopolysaccharide (LPS) Control Prostaglandin E2 Production in Astrocytes
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DOI：
10.1074/jbc.m111.327874
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发表时间：
2012-02-24
影响因子：
4.8
通讯作者：
Planas, Anna M.
中科院分区：
文献类型：
--
作者：
Font-Nieves, Miriam;Gloria Sans-Fons, M.;Planas, Anna M.
脑中的病理状况和促炎刺激诱导环氧合酶-2（考克斯-2），环氧合酶-2是花生四烯酸代谢中的关键酶，介导前列腺素类的产生，前列腺素类除其他作用外具有强的血管活性性质。尽管已经报道了低的基底脑考克斯-2表达，但是考克斯-2被促炎刺激强烈诱导，而考克斯-1是组成性表达的。然而，这些酶在前列腺素类形成中的作用取决于刺激和细胞类型。星形胶质细胞足包围着大脑微血管，释放出能够触发血管反应的分子。在这里，我们调查的调节考克斯-2的诱导和前列腺素类产生后的细菌脂多糖（LPS）在星形胶质细胞的促炎性挑战的作用。啮齿动物脑内给予LPS诱导考克斯-2主要在星形胶质细胞和小胶质细胞中强烈表达，而考克斯-1主要在小胶质细胞中表达，并且没有增加。在培养的星形胶质细胞中，LPS强烈诱导考克斯-2和微粒体前列腺素E-2（PGE（2））合酶-1，由MyD 88依赖的NF κ B B途径介导，并受丝裂原活化蛋白激酶途径的影响。对COX缺陷细胞和使用考克斯抑制剂的研究表明，LPS后，考克斯-2介导PGE（2）的高产量，并在较小程度上介导其他前列腺素类的高产量。相反，LPS以MyD 88依赖的方式下调考克斯-1，并且考克斯-1缺陷增加LPS后PGE（2）的产生。结果显示星形胶质细胞通过考克斯-2依赖性的前列腺素类物质的产生来响应LPS，主要是血管活性PGE（2），并表明考克斯-1的协同下调促进TLR-4激活后PGE（2）的产生。这些作用可能诱导脑血流对脑炎症的反应。
Pathological conditions and pro-inflammatory stimuli in the brain induce cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism mediating the production of prostanoids that, among other actions, have strong vasoactive properties. Although low basal cerebral COX-2 expression has been reported, COX-2 is strongly induced by pro-inflammatory challenges, whereas COX-1 is constitutively expressed. However, the contribution of these enzymes in prostanoid formation varies depending on the stimuli and cell type. Astrocyte feet surround cerebral microvessels and release molecules that can trigger vascular responses. Here, we investigate the regulation of COX-2 induction and its role in prostanoid generation after a pro-inflammatory challenge with the bacterial lipopolysaccharide (LPS) in astroglia. Intracerebral administration of LPS in rodents induced strong COX-2 expression mainly in astroglia and microglia, whereas COX-1 expression was predominant in microglia and did not increase. In cultured astrocytes, LPS strongly induced COX-2 and microsomal prostaglandin-E-2 (PGE(2)) synthase-1, mediated by the MyD88-dependent NF kappa B pathway and influenced by mitogen-activated protein kinase pathways. Studies in COX-deficient cells and using COX inhibitors demonstrated that COX-2 mediated the high production of PGE(2) and, to a lesser extent, other prostanoids after LPS. In contrast, LPS down-regulated COX-1 in an MyD88-dependent fashion, and COX-1 deficiency increased PGE(2) production after LPS. The results show that astrocytes respond to LPS by a COX-2-dependent production of prostanoids, mainly vasoactive PGE(2), and suggest that the coordinated down-regulation of COX-1 facilitates PGE(2) production after TLR-4 activation. These effects might induce cerebral blood flow responses to brain inflammation.