Regulation of the syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines
Regulation of the syncytin-1 promoter in human astrocytes by multiple sclerosis-related cytokines
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DOI：
10.1016/j.virol.2006.12.019
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发表时间：
2007-05-25
期刊：
影响因子：
3.7
通讯作者：
Dolei, Antonina
中科院分区：
文献类型：
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作者：
Mameli, Giuseppe;Astone, Vito;Dolei, Antonina
合胞素-1在妊娠早期起着生理作用，作为滋养细胞融合进入合体滋养层的中介，从而允许胚胎着床。此外，它在神经组织中的表达被认为与多发性硬化症(MS)的发病机制有关。Syncytin-1是人类内源性逆转录病毒(HERV)W家族ERVWE1组分的包膜糖蛋白，位于染色体7q21-22上，是MS遗传易感性的候选区域，其调控神经组织的机制尚不清楚。由于某些细胞因子与多发性硬化症的结局相关，我们研究了多发性硬化症相关细胞因子对人U-87 mg星形细胞合胞素-1启动子的调控。通过瞬时转染实验，我们观察到对MS有害的细胞因子TNFα、干扰素-γ、白介素6和白介素1激活ERVWE1启动子，而保护MS的干扰素-β则是抑制的。由于含有多种转录因子结合位点的启动子的细胞增强子区域的缺失，细胞因子的作用会减弱。特别是，我们发现，肿瘤坏死因子α能够通过位于ERVWE1启动子的增强子区域内的一个核因子-KB反应元件来激活ERVWE1启动子。电泳迁移率改变和芯片分析表明，TNFa增强了NF-kappa B的p65亚单位与其在启动子内的同源位置的结合。针对p65的siRNA可消除肿瘤坏死因子α的作用。综上所述，这些结果说明了p65在调节ERVWE1启动子和在多发性硬化症中由肿瘤坏死因子α介导的合胞素-1诱导中的作用。(C)2007 Elsevier Inc.保留所有权利。
Syncytin-1 has a physiological role during early pregnancy, as mediator of trophoblast fusion into the syncytiotrophoblast layer, hence allowing embryo implantation. In addition, its expression in nerve tissue has been proposed to contribute to the pathogenesis of multiple sclerosis (MS). Syncytin-1 is the env glycoprotein of the ERVWE1 component of the W family of human endogenous retroviruses (HERV), located on chromosome 7q21-22, in a candidate region for genetic susceptibility to MS. The mechanisms of ERVWE1 regulation in nerve tissue remain to be identified. Since there are correlations between some cytokines and MS outcome, we examined the regulation of the syncytin-1 promoter by MS-related cytokines in human U-87MG astrocytic cells. Using transient transfection assays, we observed that the MS-detrimental cytokines TNF alpha, interferon-gamma, interleukin-6, and interleukin-1 activate the ERVWE1 promoter, while the MS-protective interferon-beta is inhibitory. The effects of cytokines are reduced by the deletion of the cellular enhancer domain of the promoter that contains binding sites for several transcription factors. In particular, we found that TNF alpha had the ability to activate the ERVWE1 promoter through an NF-KB-responsive element located within the enhancer domain of the promoter. Electrophoretic mobility shift and ChIP assays showed that TNFa enhances the binding of the p65 subunit of NF-kappa B, to its cognate site within the promoter. The effect of TNF alpha is abolished by siRNA directed against p65. Taken together, these results illustrate a role for p65 in regulating the ERVWE1 promoter and in TNF alpha-mediated induction of syncytin-1 in multiple sclerosis. (C) 2007 Elsevier Inc. All rights reserved.