title: Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury.
abstract: Interferon regulatory factor (IRF)-1 is a nuclear transcription factor that induces inflammatory cytokine mediators and contributes to hepatic ischemia-reperfusion (I/R) injury. No strategies to mitigate IRF1-mediated liver damage exist. IRF2 is a structurally similar endogenous protein that competes with IRF1 for DNA binding sites in IRF-responsive target genes and acts as a competitive inhibitor. However, the role of IRF2 in hepatic injury during hypoxic or inflammatory conditions is unknown. We hypothesize that IRF2 overexpression may mitigate IRF1-mediated I/R damage. Endogenous IRF2 is basally expressed in normal livers and is mildly increased by ischemia alone. Overexpression of IRF2 protects against hepatic warm I/R injury. Furthermore, we demonstrate that IRF2 overexpression limits production of IRF1-dependent proinflammatory genes, such as IL-12, IFNβ, and inducible nitric oxide synthase, even in the presence of IRF1 induction. Additionally, isograft liver transplantation with IRF2 heterozygote knockout (IRF2(+/-)) donor grafts that have reduced endogenous IRF2 levels results in worse injury following cold I/R during murine orthotopic liver transplantation. These findings indicate that endogenous intrahepatic IRF2 protein is protective, because the IRF2-deficient liver donor grafts exhibited increased liver damage compared with the wild-type donor grafts. In summary, IRF2 overexpression protects against I/R injury by decreasing IRF1-dependent injury and may represent a novel therapeutic strategy.
authors: Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA.
authors: John R
authors: JR
authors: Klune
authors: Rajeev
authors: R
authors: Dhupar
authors: Shoko
authors: S
authors: Kimura
authors: Shinya
authors: S
authors: Ueki
authors: Jon
authors: J
authors: Cardinal
authors: Atsunori
authors: A
authors: Nakao
authors: Gary
authors: G
authors: Nace
authors: John
authors: J
authors: Evankovich
authors: Noriko
authors: N
authors: Murase
authors: Allan
authors: A
authors: Tsung
authors: David A
authors: DA
authors: Geller
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D015870:Gene Expression; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D050836:Interferon Regulatory Factor-2 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation; D008297:Male; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control
chemical_list: C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2