IFI6 Inhibits Apoptosis via Mitochondrial-Dependent Pathway in Dengue Virus 2 Infected Vascular Endothelial Cells

PLoS One. 2015 Aug 5;10(8):e0132743. doi: 10.1371/journal.pone.0132743. eCollection 2015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Cell Line
  • Dengue / virology
  • Dengue Virus*
  • Down-Regulation
  • Endothelial Cells / metabolism*
  • Endothelial Cells / virology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / virology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / virology
  • Humans
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction / genetics*
  • Up-Regulation
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • BCL2 protein, human
  • IFI6 protein, human
  • Mitochondrial Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • bcl-2-Associated X Protein

Grants and funding

This work was supported by the National Natural Science Foundation of China (no. 30872350 and no. 31370870), http://isis.nsfc.gov.cn; the Natural Science Foundation of Guangdong Province (no. s81510008901000017, no. s2012010009050 and no. s2013020013000), http://gdsf.gdstc.gov.cn; the Guangdong Province Scientific Technology Project (no. 2010B050700008 and no. 2011B040300022), http://www.gdstc.gov.cn; the Guangzhou City Scientific Technology Project (no. 2011J4100084 and no. 2008Z1-E221), http://apply.gzsi.gov.cn/; The Fundamental Research Funds for the Central Universities (no. 10YKPY31), http://mso.sysu.edu.cn; and the Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology (no. 2013A061401007), http://www.gdstc.gov.cn. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.