title: The transcription factor interferon regulatory factor-1 mediates liver damage during ischemia-reperfusion injury.
abstract: Hepatic ischemia occurs in the settings of trauma, transplantation, and elective liver resections. The initiating events that account for local organ damage are only partially understood. Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of a number of genes involved in both innate and acquired immunity; however, its function in liver injury is unknown. Therefore, the purpose of this study was to investigate the role of IRF-1 in hepatic ischemia-reperfusion (I/R) injury. In C57BL/6 mice undergoing 60 min of hepatic ischemia, IRF-1 protein expression increased as early as 1 h after reperfusion. IRF-1 knockout mice were significantly protected from hepatic I/R-induced damage compared with their wild-type controls. Hepatic I/R injury resulted in marked activation of the MAP kinase c-Jun NH(2)-terminal kinase (JNK) in wild-type mice but not IRF-1 knockout mice. IRF-1 knockout mice also exhibited significantly lower hepatic expression of TNF-alpha, IL-6, ICAM-1, and inducible nitric oxide synthase (iNOS) mRNA. Adenoviral delivery of IRF-1 into C57BL/6 mice resulted in increased liver damage even without an ischemic insult. This injury was associated with increased JNK activation and hepatic iNOS expression. Because IRF-1 contributed to liver injury, we also examined for inflammatory signals that regulated IRF-1 gene expression in cultured hepatocytes. Whereas IFN-gamma and IFN-beta were strong inducers of IRF-1 mRNA (>10-fold) in a time- and dose-dependent manner, TNF-alpha and IL-1beta also induced IRF-1 mRNA to a lesser extent (2- to 3-fold). IL-6 and lipopolysaccharide had no effect on IRF-1 expression. This study demonstrates that IRF-1 exerts a harmful role in hepatic I/R injury by modulating the expression of multiple inflammatory mediators. We further show that IRF-1-mediated injury involves the activation of JNK and that hepatocellular IRF-1 expression itself is regulated by specific cytokines.
authors.affiliation: Department of Surgery, University of Pittsburgh, PA 15213, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
authors.forename: Michael T
authors.initials: MT
authors.lastname: Stang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ikeda
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Critchlow
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Izuishi
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
authors.forename: Meagan H
authors.initials: MH
authors.lastname: Chan
authors.forename: Geetha
authors.initials: G
authors.lastname: Jeyabalan
authors.forename: John H
authors.initials: JH
authors.lastname: Yim
authors.forename: David A
authors.initials: DA
authors.lastname: Geller
mesh_terms: D000818:Animals; D008099:Liver / Q000098:blood supply* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000276:immunology*
chemical_list: D014157:Transcription Factors