Stroke is one of the most frequent causes of death and disability worldwide. Cerebral ischemia is the major insult of stroke and induces acute inflammation by triggering excessive production of proinflammatory cytokines, leading to the exacerbation of primary brain damage. Toll-like receptor (TLR)- and nitric oxide-mediated signaling pathways have been identified under ischemic stress. However, the interaction between these two pathways in controlling proinflammatory cytokines has not been well addressed during cerebral ischemia. Adult male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) for stroke induction. The MCAO procedure resulted in a significant infarct in the brain after 24h. The infarcted side of the brain had marked elevation of TNF-α gene and protein expression, compared to the sham brain. The expression of CD14, a co-receptor of TLR4, was induced by MCAO, while the expression of TLR4 remained unchanged. The levels of inducible nitric oxide synthase (iNOS) and nitrotyrosine were also upregulated in the infracted side of the brain. Correspondingly, exposing murine microglial BV2 cells to hypoxia (1% O2) for 20h resulted in an increased expression of TNF-α, CD14, iNOS, and nitrotyrosine. When BV2 cells were treated with l-canavanine, an iNOS selective inhibitor, the elevation of TNF-α and CD14 induced by hypoxia was inhibited. This inhibition was associated with an increase of IκB. These results suggest that the upregulation of TNF-α production in ischemic stroke is partially through increasing iNOS, and then CD14 expression leading to the activation of the NF-κB pathway in microglia.

译文

:中风是世界范围内最常见的死亡和残疾原因之一。脑缺血是中风的主要损害,并通过触发促炎性细胞因子的过量产生而诱发急性炎症,从而导致原发性脑损伤的加剧。在缺血性应激下已经确定了Toll样受体(TLR)和一氧化氮介导的信号通路。然而,在脑缺血期间,这两种途径之间在控制促炎性细胞因子中的相互作用尚未得到很好的解决。对成年雄性C57BL / 6小鼠进行大脑中动脉闭塞(MCAO)诱导中风。 24小时后,MCAO程序导致大脑严重梗塞。与假脑相比,脑梗死一侧的TNF-α基因和蛋白质表达明显升高。 MCAO诱导TLR4的共受体CD14的表达,而TLR4的表达保持不变。诱导型一氧化氮合酶(iNOS)和硝基酪氨酸的水平在大脑的患侧也被上调。相应地,将鼠小神经胶质BV2细胞暴露于低氧(1%O2)条件下20小时会导致TNF-α,CD14,iNOS和硝基酪氨酸的表达增加。当用iNOS选择性抑制剂l-canavanine处理BV2细胞时,缺氧诱导的TNF-α和CD14升高被抑制。这种抑制与IκB的增加有关。这些结果表明缺血性中风中TNF-α产生的上调部分是通过增加iNOS,然后是CD14表达导致小胶质细胞中NF-κB途径的激活。

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