Upregulation of Ras homolog enriched in the brain (Rheb) in lipopolysaccharide-induced neuroinflammation
Upregulation of Ras homolog enriched in the brain (Rheb) in lipopolysaccharide-induced neuroinflammation
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脂多糖诱导的神经炎症中脑部富集的 Ras 同源物 (Rheb) 的上调
DOI：
10.1016/j.neuint.2013.01.025
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发表时间：
2013-03-01
影响因子：
4.2
通讯作者：
Gao, Yilu
中科院分区：
文献类型：
--
作者：
Cao, Maohong;Tan, Xiang;Gao, Yilu
脑内丰富的RAS同源物(Rheb)是Ras GTPase的同系物，通过哺乳动物靶标雷帕霉素(MTOR)调节细胞的生长、增殖和细胞周期。近年来，Rheb的激活不仅促进了细胞的增殖和分化，而且还促进了细胞对各种毒性刺激的凋亡。然而，Rheb在中枢神经系统(CNS)中的作用目前还知之甚少。为了阐明Rheb是否参与中枢神经系统损伤，我们采用内毒素(LPS)腹侧注射的方法复制了成年大鼠的神经炎性模型。用Western blotting和免疫组织化学方法观察Rheb在大脑皮层的表达。免疫荧光双重染色显示，Rheb主要分布在活跃的星形胶质细胞和神经元中。增殖细胞核抗原和活化的caspase-3表达上调，并与Rheb共标记，提示Rheb可能与内毒素诱导的炎症反应后星形胶质细胞的增殖和神经元的凋亡有关。此外，我们还发现Cyclin D1和CDK4的表达谱与Rheb的表达谱具有时空依赖性。最后，用siRNA敲除Rheb，并用雷帕霉素或洛伐他汀治疗，结果表明，星形胶质细胞的增殖不仅减少，而且对神经元具有保护作用。根据我们的数据，我们认为Rheb可能在内毒素引起的神经炎症后的生理和病理功能中发挥重要作用，这可能为治疗神经炎症提供一个潜在的靶点。(C)2013爱思唯尔有限公司。保留所有权利。
Ras homolog enriched in the brain (Rheb) is a homolog of Ras GTPase that regulates cell growth, proliferation, and cell cycle via mammalian target of rapamycin (mTOR). Recently, it has been confirmed that Rheb activation not only promotes cellular proliferation and differentiation but also enhances cellular apoptosis in response to diverse toxic stimuli. However, the function of Rheb in the central nervous system (CNS) is still with limited understanding. To elaborate whether Rheb was involved in CNS injury, we performed a neuroinflammatory model by lipopolysaccharide (LPS) lateral ventral injection in adult rats. Upregulation of Rheb was observed in the brain cortex by performing western blotting and immunohistochemistry. Double immunofluorescent staining demonstrated that Rheb was mainly in active astrocytes and neurons. PCNA and active caspase-3 were upregulated, and co-labeling with Rheb, which indicated that Rheb might be relevant to astrocytic proliferation and neuronal apoptosis following the inflammatory response by LPS-induced. Furthermore, we also found that the expression profiles of cyclinD1 and CDK4 were parallel with that of Rheb in a time-space dependent manner. Finally, knocking down Rheb by siRNA and treatment with rapamycin or lovastatin showed that not only astrocytic proliferation decreased but also neuronal protection. Based on our data, we suggested that Rheb might play an important role in physiological and pathological functions following neuroinflammation caused by LPS, which might provide a potential target to the treatment of neuroinflammation. (C) 2013 Elsevier Ltd. All rights reserved.