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Critical role of interferon regulatory factor‐1 in murine liver transplant ischemia reperfusion injury
Author(s) -
Ueki Shinya,
Dhupar Rajeev,
Cardinal Jon,
Tsung Allan,
Yoshida Junichi,
Ozaki Kikumi S.,
Klune John R.,
Murase Noriko,
Geller David A.
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23501
Subject(s) - irf1 , hepatology , reperfusion injury , liver transplantation , liver injury , viaspan , hepatocyte , apoptosis , interferon , transplantation , biology , immunology , transcription factor , medicine , cancer research , ischemia , gene , biochemistry , in vitro
Interferon regulatory factor‐1 (IRF‐1) is a transcription factor that regulates gene expression during immunity. We hypothesized that IRF‐1 plays a pivotal role in liver transplant (LTx) ischemia/reperfusion (I/R) injury. Mouse orthotopic LTx was conducted after 24 hours cold storage in University of Wisconsin (UW) solution in wildtype (WT) C57BL/6 and IRF‐1 knockout (KO) mice. IRF‐1 deficiency in liver grafts, but not in recipients, resulted in significant reduction of hepatocyte apoptosis and liver injury, as well as improved survival. IRF‐1 mRNA up‐regulation was typically seen in graft hepatocytes in WT→WT LTx. Deficiency of IRF‐1 signaling in graft resulted in significantly reduced messenger RNA (mRNA) levels for death ligands and death receptors in hepatocytes, as well as decreased caspase‐8 activities, indicating that IRF‐1 mediates death ligand‐induced hepatocyte death. Further, a smaller but significant IRF‐1 mRNA up‐regulation was seen in WT graft nonparenchymal cells (NPC) and associated with interferon gamma (IFN‐γ) mRNA up‐regulation exclusively in NPC. IFN‐γ mRNA was significantly reduced in IRF‐1 KO graft. Thus, IRF‐1 in graft hepatocytes and NPC has distinct effects in hepatic I/R injury. However, LTx with chimeric liver grafts showed that grafts lacking hepatocellular IRF‐1 had better protection compared with those lacking IRF‐1 in NPC. The study identifies a critical role for IRF‐1 in liver transplant I/R injury. (H EPATOLOGY 2010.)