Down-regulation of microglial cyclo-oxygenase-2 and inducible nitric oxide synthase expression by lipocortin 1
Down-regulation of microglial cyclo-oxygenase-2 and inducible nitric oxide synthase expression by lipocortin 1
复制标题
DOI：
10.1038/sj.bjp.0702423
复制
发表时间：
1999-03-01
影响因子：
7.3
通讯作者：
Levi, G
中科院分区：
文献类型：
--
作者：
Minghetti, L;Nicolini, A;Levi, G
1激活的小胶质细胞被认为在大多数脑病理中发挥积极作用，在此期间，它们可以促进宿主的防御和修复，但也有助于建立组织损伤。这些作用在很大程度上是由小胶质细胞分泌的产物介导的，其中包括前列腺素(PGs)和一氧化氮(NO)。2据报道，抗炎蛋白脂皮质素1(Lipocortin 1，LC1)具有神经保护作用，可在多种脑结构中被糖皮质激素诱导，并在小胶质细胞中优先表达。3我们先前的研究表明，细菌内毒素通过诱导关键酶环氧合酶-2(COX-2)和诱导型一氧化氮合酶(INOS)的表达来强烈刺激原代培养的大鼠小胶质细胞产生PGE(2)和NO。4地塞米松(DEX，1-100 nM)和LCL衍生的N-末端多肽(肽Ac2-26，1-100 1.18 mU·ml(-1))可剂量依赖性地抑制LPS刺激的小胶质细胞产生PGE_2和NO。地塞米松对NO的抑制作用和多肽对NO和PGE_1合成的抑制作用，可被针对人LC_1 N端的特异性抗血清部分阻断。5 Western印迹实验表明，地塞米松(100 NM)和Ac2-26(100 mU·g·ml~(-1))能有效下调LPS诱导的小胶质细胞COX-2和iNOS的表达。6综上所述，我们的研究结果支持了LC1可能通过自分泌和旁分泌机制限制小胶质细胞激活从而促进神经保护的假说。
1 Activated microglial cells are believed to play an active role in most brain pathologies, during which they can contribute to host defence and repair but also to the establishment of tissue damage. These actions are largely mediated by microglial secretory products, among which are prostaglandins (PGs) and nitric oxide (NO).2 The anti-inflammatory protein, lipocortin 1 (LC1) was reported to have neuroprotective action and to be induced by glucocorticoids in several brain structures, with a preferential expression in microglia. In this paper we tested whether the neuroprotective effect of LC1 could be explained by an inhibitory effect on microglial activation.3 We have previously shown that bacterial endotoxin (LPS) strongly stimulates PGE(2) and NO production in rat primary microglial cultures, by inducing the expression of the key enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), respectively.4 Dexamethasone (DEX, 1-100 nM) and LCl-derived N-terminus peptide (peptide Ac2-26, 1-100 1.18 mu g ml(-1)) dose-dependently inhibited the production of both PGE2 and NO from LPS-stimulated microglia. The inhibitory effects of DEX on NO and of the peptide on NO and PGE, synthesis were partially abrogated by a specific antiserum, raised against the N-terminus of human LC1. The peptide Ac2-26 did not affect arachidonic acid release from control and LPS-stimulated microglial cultures.5 Western blot experiments showed that the LPS-induced expression of COX-2 and iNOS was effectively down-regulated by DEX (100 nM) and peptide Ac2-26 (100 mu g ml(-1)).6 In conclusion, our findings support the hypothesis that LC1 may foster neuroprotection by limiting microglial activation, through autocrine and paracrine mechanisms.