IFI6 Inhibits Apoptosis via Mitochondrial-Dependent Pathway in Dengue Virus 2 Infected Vascular Endothelial Cells.
IFI6 Inhibits Apoptosis via Mitochondrial-Dependent Pathway in Dengue Virus 2 Infected Vascular Endothelial Cells.
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IFI6 通过线粒体依赖性途径抑制登革热病毒 2 感染的血管内皮细胞的细胞凋亡
DOI：
10.1371/journal.pone.0132743
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Huang J
中科院分区：
文献类型：
--
作者：
Qi Y;Li Y;Zhang Y;Zhang L;Wang Z;Zhang X;Gui L;Huang J
登革出血热(DHF)/登革休克综合征(DSS)是一种需要有效治疗的致命传染病。登革病毒(DENV)诱导的干扰素刺激基因(ISGs)具有抗病毒作用。在本实验室前期研究的人脐静脉内皮细胞中，干扰素-α诱导基因6(IFI6)在基因芯片中表达上调。然而，人们对其功能的认识还不够全面。在这项研究中，我们证实IFI6在原代HUVECs和EA.hy926细胞株的DENV感染中都被显著诱导。获得了过表达IFI6(IFI6+/+)或基因敲除(IFI6-/-)的重组EA.hy926细胞。感染后24~48h，iFI6+/+细胞中caspase-3和固有的凋亡相关蛋白caspase-9表达下调，而iFI6-/-细胞中caspase-3和内源性凋亡相关蛋白caspase-9表达上调。JC-1荧光染色显示，与DENV共同孵育48h后，IFI6+/+细胞线粒体膜电位(Δψ(M))更稳定，而IFI6-/-细胞线粒体膜电位降低。我们观察到，在IFI6+/+细胞中，Bcl2的表达增加，而在IFI6-/-细胞中的表达降低。相反，Bax在IFI6+/+细胞中表达降低，在IFI6-/-细胞中表达增加。推测IFI6的抗凋亡作用是通过调节血管内皮细胞感染DENV过程中bcl2/bax表达和抑制Δψ(M)去极化之间的流变性平衡来实现的。此外，促凋亡蛋白X连锁凋亡抑制因子1(XAF1)的表达上调并诱导DENV2感染的血管内皮细胞发生凋亡，但XAF1与IFI6登革病毒诱导的血管内皮细胞凋亡的关系有待进一步研究。
Dengue hemorrhagic fever (DHF)/Dengue shock syndrome (DSS) is a fatal infectious disease that demands an effective treatment. Interferon (IFN)-stimulated genes (ISGs) induced by dengue virus (DENV) exert antiviral effects. Among ISGs, IFN-α inducible gene 6 (IFI6) was increased in DENV infected human umbilical vascular endothelial cells (HUVECs) by microarray analysis in our previous study. However, its function is incompletely understood. In this study, we confirmed that IFI6 was markedly induced in DENV infection of both primary HUVECs and EA.hy926 cell lines. Recombinant EA.hy926 cell lines in which IFI6 was either over-expressed (IFI6+/+) or knocked-down (IFI6-/-) were generated. The activation of caspase-3 and intrinsic apoptosis-related protein caspase-9 were down-regulated in IFI6+/+ but up-regulated in IFI6-/- cells at 24–48 hrs post-infection. After incubation with DENV for 48 hrs, the mitochondrial membrane potential (Δψ(m)) was more stable in IFI6+/+ cells but reduced in IFI6-/- cells, as assayed by fluorescence staining with JC-1. We observed that Bcl-2 expression was increased in IFI6+/+ and decreased in IFI6-/- cells. By contrast, Bax expression was decreased in IFI6+/+ and increased in IFI6-/- cells. It is presumed that the anti-apoptotic function of IFI6 is expressed by regulating the rheostatic balance between bcl-2/bax expression and inhibition of Δψ(m) depolarization during DENV infection of vascular endothelial cells(VECs). In addition, the pro-apoptotic protein X-linked Inhibitor of Apoptosis (XIAP)-Associated Factor 1(XAF1) expression had been reported to be up-regulated and led to the induction of apoptosis in DENV2-infected VECs,but the relationship between XAF1 and IFI6 dengue virus-induced apoptosis in VECs warrants further study.