title: IFI16 mediates soluble Flt-1 and endoglin production by trophoblast cells.
abstract: OBJECTIVE
  Preeclampsia is a serious pregnancy-specific hypertensive syndrome that is characterized by widespread maternal endothelial dysfunction. Previous studies have shown that increased levels of circulating cell-free fetal DNA in women with preeclampsia correspond to the degree of disease severity; however, it is unknown whether this DNA is a key signal that contributes to the development of preeclampsia. The detection of DNA is critical to appropriate innate immune responses. The interferon-inducible protein 16 (IFI16) - a member of the HIN-200 family - is an innate immune receptor for intracellular DNA, which is implicated in the control of cell growth, apoptosis, angiogenesis, and immunomodulation; however, its role in preeclampsia remains unresolved. Here, we tested the hypothesis that this DNA can activate IFI16 in the placentas of women with preeclampsia and is sufficient to induce soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) production.
  
  
  METHODS
  We characterized IFI16 in severe preeclamptic placentas and assessed whether DNA increased the release of sFlt-1 and sEng from trophoblast cells and placental explants. Furthermore, we determined whether IFI16 was involved in DNA-induced sFlt-1 and sEng production.
  
  
  RESULTS
  Placental immunoreactivity and protein levels of IFI16 were significantly increased in women with preeclampsia compared to matched control women. Treatment of human trophoblasts with the IFI16 agonist poly(dA:dT) significantly increased IFI16 levels. Furthermore, poly(dA:dT) induced sFlt-1 and sEng production by human trophoblasts in an IFI16-dependent manner.
  
  
  CONCLUSIONS
  We conclude that trophoblast cells respond to cell-free fetal DNA through the IFI16 receptor, resulting in the production of the preeclampsia-related antiangiogenic factors sFlt-1 and sEng.
authors.affiliation: aKey Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine bThe First Hospital of Jilin University, Jilin University, Changchun, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Hu
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.forename: Shui-Xing
authors.initials: SX
authors.lastname: Yu
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Chong-Tao
authors.initials: CT
authors.lastname: Du
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Yang
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis*; D002478:Cells, Cultured; D000071063:Endoglin; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010920:Placenta / Q000276:immunology / Q000378:metabolism*; D011067:Poly dA-dT / Q000494:pharmacology; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D014176:Protein Biosynthesis / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D015398:Signal Transduction; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; C076700:IFI16 protein, human; D011067:Poly dA-dT; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1