Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania.
Glia. 2014 Feb;62(2):159-70. doi: 10.1002/glia.22594. Epub 2013 Dec 5.
Reactive oxygen species (ROS) have been implicated in various types of CNS damage, including stroke. We used a cultured astrocyte model to explore mechanisms of survival of CNS cells following ROS damage. We found that pretreatment with leukemia inhibitory factor (LIF) preserves astrocytes exposed to toxic levels of t-BHP by inhibiting an increase in intracellular ROS following t-BHP treatment. Astrocytes lacking functional Stat3 did not benefit from the pro-survival or antioxidant effects of LIF. Inhibition of mitochondrial uncoupling protein 2 (UCP2) using a chemical inhibitor or siRNA abrogates the prosurvival effects of LIF, indicating a critical role for UCP2 in modulation of mitochondrial ROS production in survival following ROS exposure. LIF treatment of astrocytes results in increased UCP2 mRNA that is accompanied by an increase in Stat3 binding to the UCP2 promoter region. Although treatment with LIF alone did not increase UCP2 protein, a combination of LIF treatment and ROS stress led to increased UCP2 protein levels. We conclude that LIF protects astrocytes from ROS-induced death by increasing UCP2 mRNA, allowing cells to respond to ROS stress by rapidly producing UCP2 protein that ultimately decreases endogenous mitochondrial ROS production.
活性氧 (ROS) 与各种类型的中枢神经系统损伤有关，包括中风。我们使用培养的星形胶质细胞模型来探索 ROS 损伤后中枢神经系统细胞存活的机制。我们发现，白血病抑制因子 (LIF) 的预处理通过抑制 t-BHP 处理后细胞内 ROS 的增加来保护暴露于有毒 t-BHP 水平的星形胶质细胞。缺乏功能性 Stat3 的星形胶质细胞不能从 LIF 的促生存或抗氧化作用中受益。使用化学抑制剂或 siRNA 抑制线粒体解偶联蛋白 2 (UCP2) 会消除 LIF 的促生存作用，表明 UCP2 在 ROS 暴露后调节线粒体 ROS 产生对于生存至关重要。LIF 处理星形胶质细胞会导致 UCP2 mRNA 增加，同时 Stat3 与 UCP2 启动子区域的结合增加。尽管单独使用 LIF 治疗不会增加 UCP2 蛋白，但 LIF 治疗和 ROS 应激的组合会导致 UCP2 蛋白水平增加。我们得出的结论是，LIF 通过增加 UCP2 mRNA 来保护星形胶质细胞免受 ROS 诱导的死亡，使细胞能够通过快速产生 UCP2 蛋白来应对 ROS 应激，最终降低内源性线粒体 ROS 产生。
