FOXO3a inhibits TNF-α- and IL-1β-induced astrocyte proliferation:Implication for reactive astrogliosis.
FOXO3a inhibits TNF-α- and IL-1β-induced astrocyte proliferation:Implication for reactive astrogliosis.
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DOI：
10.1002/glia.21134
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发表时间：
2011-04
期刊：
影响因子：
6.2
通讯作者：
Zheng, Jialin
中科院分区：
文献类型：
--
作者：
Cui, Min;Huang, Yunlong;Tian, Changhai;Zhao, Yong;Zheng, Jialin
反应性星形胶质细胞增生是神经退行性疾病的病理标志之一。炎性细胞因子如TNF-α和IL-1β已被证明介导神经退行性疾病中的反应性星形胶质细胞增生;然而，其分子机制仍不清楚。在这项研究中，我们研究了转录因子FOXO 3a对星形胶质细胞增殖的作用，这是严重反应性星形胶质细胞增生的一个主要方面。我们的研究结果证实，TNF-α和IL-1β增加星形胶质细胞增殖，通过Ki 67和BrdU免疫染色确定。此外，我们发现，苦参碱介导的星形胶质细胞增殖伴随着增加的磷酸化和减少的FOXO 3a的核表达。颅内注射TNF-α和IL-1β可诱导星形胶质细胞增殖和肥大，这与星形胶质细胞中Foxo 3a的核表达减少有关。为了确定FOXO 3a在星形胶质细胞增殖中的功能，用腺病毒过表达野生型FOXO 3a，其随后上调p27 Kip 1和Gadd 45 α，并显著抑制苦参碱诱导的星形胶质细胞增殖。相反，显性负性FOXO 3a的过表达降低了p27 Kip 1，上调了细胞周期蛋白D1，促进了星形胶质细胞增殖。沿着相同的线，从Foxo 3a缺失小鼠分离的星形胶质细胞具有更高的增殖潜力。响应于细胞因子的颅内注射，Foxo 3a缺失小鼠在体内表现出严重的星形胶质细胞增生。总之，FOXO 3a是重要的抑制星形胶质细胞增殖在促炎细胞因子刺激和FOXO 3a的功能丧失可能是负责星形胶质细胞的增殖，在严重形式的反应性星形胶质细胞增生。了解FOXO 3a在反应性星形胶质细胞增生中的关键调节作用可能为神经炎症提供新的治疗靶点。
Reactive astrogliosis is one of the pathological hallmarks of neurodegenerative diseases. Inflammatory cytokines, such as TNF-α and IL-1β, have been shown to mediate the reactive astrogliosis in neurodegenerative diseases; however, the molecular mechanism remains unclear. In this study, we investigated the role of transcription factor FOXO3a on astrocyte proliferation, one primary aspect of severe reactive astrogliosis. Our results confirmed that TNF-α and IL-1β increased astrocyte proliferation, as determined by Ki67 and BrdU immunostaining. Furthermore, we found that cytokine-mediated astrocyte proliferation was accompanied by an increase of the phosphorylation and reduced nuclear expression of FOXO3a. Intracranial injection of TNF-α and IL-1β induced astrocyte proliferation and hypertrophy, which was associated with reduced nuclear expression of Foxo3a in astrocytes. To determine the function of FOXO3a in astrocyte proliferation, wild type FOXO3a was overexpressed with adenovirus, which subsequently upregulated p27Kip1 and Gadd45α, and significantly inhibited cytokine-induced astrocyte proliferation. In contrast, overexpression of dominant negative FOXO3a decreased p27Kip1, upregulated cyclin D1 and promoted astrocyte proliferation. Along the same line, astrocytes isolated from Foxo3a-null mice have higher proliferative potential. In response to intracranial injection of cytokines, Foxo3a-null mice manifested severe astrogliosis in vivo. In conclusion, FOXO3a is important in restraining astrocyte proliferation during proinflammatory cytokine stimulation and loss of function of FOXO3a may be responsible for the proliferation of astrocytes in the severe form of reactive astrogliosis. Understanding the key regulatory role of FOXO3a in reactive astrogliosis may provide a novel therapeutic target during neuroinflammation.
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影响因子：
64.5
作者：
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通讯作者：
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DOI：
10.1038/mt.2009.44
发表时间：
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期刊：
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