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.

A Critical Role for IFN Regulatory Factor 1 in NKT Cell-Mediated Liver Injury Induced by α-Galactosylceramide

“…IRF-1 has been shown to be expressed in cultures of primary hepatocytes in response to inflammatory cytokine IFN-a/b, IFN-g, TNF-a, and IL-1b (25). Recent work in our laboratory suggested that IRF-1 contributes to liver damage induced by warm hepatic I/R injury (26,27). Furthermore, we have also shown that IRF-1 plays a critical role in liver transplant preservation injury (27,28).…”

“…Recent evidence also suggests an important role of NKT cells in initiating injury following hepatic warm I/R, as well as limiting liver graft survival following transplantation (12,13,15,41). We have previously shown that IRF-1 expression is upregulated in the liver following both warm and cold I/R injury, and increased IRF-1 expression contributes to the hepatic damage whereas the IRF-1 knockout mice were protected from the injury (26,27). Importantly, it was the specific presence of IRF-1 in the donor liver graft, but not the recipient host, that accounted for the liver damage (27,28).…”

“…In murine macrophages, IRF-1 has been shown to control the transcription of iNOS in response to IFN-g and LPS stimulation (32,33). We have previously shown that iNOS is upregulated by IRF-1 in cultured murine hepatocytes (26). Increased iNOS activity in the liver has been implicated as a contributing factor for a variety of liver diseases, such as hepatic I/R, hemorrhagic shock, and alcoholic hepatitis (34).…”

Evaluating mRNA Expression Levels of the TLR4/IRF5 Signaling Axis During Hepatic Ischemia-Reperfusion Injuries

“…6 Several reports have investigated the roles of IRF1 and IRF3 in liver IRI. 7,8 However, to the best of our knowledge, there are no data supporting the involvement of IRF5 during liver IRI. Therefore, this study was carried out to investigate the role of the TLR4/IRF5 signaling pathway in the hepatic IRI model, by evaluating mRNA expression levels of TLR4/IRF5 axis and its downstream genes, including tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β).…”

Inhibition of Intrinsic Interferon-γ Function Prevents Neointima Formation After Balloon Injury

“…5 This cytokine is expressed at high levels in vascular lesions and regulates functions and properties of all of the cell types in vascular wall 6,7 by activating signal transducer and activator of transcription-1 (STAT1) and IFN regulatory factor-1 (IRF-1), the major transcriptional activator mediating IFN-␥ signal. 5 IFN-␥ is a known regulator of intercellular adhesion molecule (ICAM)-1 8,9 and plateletderived growth factor (PDGF) ␤-receptor (PDGFR-␤), 4,10 molecules that mediate SMC proliferation. However, IFN-␥ also has anti-inflammatory actions, such as interleukin-8 induction, in a range of cell types 7 and antiproliferative action in cultured SMCs.…”