The antiviral cytokine interferon-gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation.
The antiviral cytokine interferon-gamma restricts neural stem/progenitor cell proliferation through activation of STAT1 and modulation of retinoblastoma protein phosphorylation.
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DOI：
10.1002/jnr.23987
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发表时间：
2017-08
影响因子：
4.2
通讯作者：
O'Donnell LA
中科院分区：
文献类型：
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作者：
Kulkarni A;Scully TJ;O'Donnell LA
神经干/祖细胞（NPSC）表达许多炎性细胞因子的受体，根据发育阶段和炎性介质的环境对分化和增殖具有不同的影响。在原代神经元和星形胶质细胞中，我们最近发现，干扰素γ（IFNγ），一种控制和清除许多中枢神经系统（CNS）感染所需的强效抗病毒细胞因子，可以根据细胞类型和激活的细胞内信号分子的特征不同影响细胞存活和细胞周期进程。在这里，我们发现IFNγ通过肿瘤抑制因子视网膜母细胞瘤蛋白（pRb）的去磷酸化来抑制原代NSPCs的增殖，这依赖于信号转导和转录激活因子-1（STAT 1）信号通路的激活。我们的研究结果表明：i）IFNγ以剂量依赖性方式抑制神经球生长和增殖速率; ii）IFNγ通过晚期G1/S期限制阻断细胞周期进程; iii）IFNγ诱导STAT 1和STAT 3的磷酸化和表达; iv）IFNγ降低细胞周期蛋白E/cdk 2的表达，并降低丝氨酸残基795上的细胞周期蛋白D1和pRb的磷酸化;和v）IFNγ对NSPC增殖、细胞周期蛋白表达和pRb磷酸化的作用是STAT 1依赖性的。这些数据确定了IFNγ可有助于减少炎症条件下NSPC增殖的机制。进一步阐明炎性细胞因子对NSPC生长的影响可以提高我们对CNS感染和其他炎症事件如何破坏脑发育和NSPC功能的理解。© 2016作者。《神经科学研究杂志》（Journal of Neuroscience Research）由Wiley Periodicals，Inc.出版。
Neural stem/progenitor cells (NPSCs) express receptors for many inflammatory cytokines, with varying effects on differentiation and proliferation depending on the stage of development and the milieu of inflammatory mediators. In primary neurons and astrocytes, we recently showed that interferon gamma (IFNγ), a potent antiviral cytokine that is required for the control and clearance of many central nervous system (CNS) infections, could differentially affect cell survival and cell cycle progression depending upon the cell type and the profile of activated intracellular signaling molecules. Here, we show that IFNγ inhibits proliferation of primary NSPCs through dephosphorylation of the tumor suppressor Retinoblastoma protein (pRb), which is dependent on activation of signal transducers and activators of transcription‐1 (STAT1) signaling pathways. Our results show i) IFNγ inhibits neurosphere growth and proliferation rate in a dose‐dependent manner; ii) IFNγ blocks cell cycle progression through a late‐stage G1/S phase restriction; iii) IFNγ induces phosphorylation and expression of STAT1 and STAT3; iv) IFNγ decreases cyclin E/cdk2 expression and reduces phosphorylation of cyclin D1 and pRb on serine residue 795; and v) the effects of IFNγ on NSPC proliferation, cell cycle protein expression, and pRb phosphorylation are STAT1‐dependent. These data define a mechanism by which IFNγ could contribute to a reduction in NSPC proliferation in inflammatory conditions. Further delineation of the effects of inflammatory cytokines on NSPC growth could improve our understanding of how CNS infections and other inflammatory events disrupt brain development and NSPC function. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.