Critical role of interferon regulatory factor-1 in murine liver transplant ischemia reperfusion injury.
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-gamma) mRNA up-regulation exclusively in NPC. IFN-gamma 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.
Department of Surgery, Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Shinya
S
Ueki
Rajeev
R
Dhupar
Jon
J
Cardinal
Allan
A
Tsung
Junichi
J
Yoshida
Kikumi S
KS
Ozaki
John R
JR
Klune
Noriko
N
Murase
David A
DA
Geller
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D016031:Liver Transplantation / Q000009:adverse effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology*; D015854:Up-Regulation
D050856:Interferon Regulatory Factor-1; D012333:RNA, Messenger; D007371:Interferon-gamma