title: Interferon regulatory factor 9 is a key mediator of hepatic ischemia/reperfusion injury.
abstract: OBJECTIVE
  Hepatic ischemia/reperfusion (I/R) injury is characterized by anoxic cell injury and the generation of inflammatory mediators, leading to hepatic parenchymal cell death. The activation of interferon regulatory factors (IRFs) has been implicated in hepatic I/R injury, but the role of IRF9 in this progression is unclear.
  
  
  METHODS
  We investigated the function and molecular mechanisms of IRF9 in transgene and knockout mice subjected to warm I/R of the liver. Isolated hepatocytes from IRF9 transgene and knockout mice were subjected to hypoxia/reoxygenation (H/R) injury to determine the in vitro effects of IRF9.
  
  
  RESULTS
  The injuries were augmented in IRF9-overexpressing mice that were subjected to warm I/R of the liver. In contrast, a deficiency in IRF9 markedly reduced the necrotic area, serum alanine amino transferase/aspartate amino transferase (ALT/AST), immune cell infiltration, inflammatory cytokine levels, and hepatocyte apoptosis after liver I/R. Sirtuin (SIRT) 1 levels were significantly higher and the acetylation of p53 was decreased in the IRF9 knockout mice. Notably, IRF9 suppressed the activity of the SIRT1 promoter luciferase reporter and deacetylase activity. Liver injuries were significantly more severe in the IRF9/SIRT1 double knockout (DKO) mice in the I/R model, eliminating the protective effects observed in the IRF9 knockout mice.
  
  
  CONCLUSIONS
  IRF9 has a novel function of inducing hepatocyte apoptosis after I/R injury by decreasing SIRT1 expression and increasing acetyl-p53 levels. Targeting IRF9 may be a potential strategy for ameliorating ischemic liver injury after liver surgery.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Pi-Xiao
authors.initials: PX
authors.lastname: Wang
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China.
authors.forename: Song
authors.initials: S
authors.lastname: Tian
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute, Wuhan University, Wuhan, China. Electronic address: lihl@whu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology
chemical_list: D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; C494228:Isgf3g protein, mouse
keywords: Hepatic injury; IRF9; Ischemia/reperfusion