A critical role for IFN regulatory factor 1 in NKT cell-mediated liver injury induced by α-galactosylceramide

NKT cells are remarkably abundant in mouse liver. Compelling experimental evidence has suggested that NKT cells are involved in the pathogenesis of many liver diseases. Activation of NKT cells with α-galactosylceramide (α-GalCer) causes liver injury through mechanisms that are not well understood. We undertook studies to characterize the key pathways involved in α-GalCer-induced liver injury. We found that expression of the transcription factor IFN regulatory factor 1 (IRF-1) in mouse liver was dramatically upregulated by α-GalCer treatment. Neutralization of either TNF-α or IFN-γ inhibited α-GalCer-mediated IRF-1 upregulation. α-GalCer-induced liver injury was significantly suppressed in IRF-1 knockout mice or in wild-type C56BL/6 mice that received a microRNA specifically targeting IRF-1. In contrast, overexpression of IRF-1 greatly potentiated α-GalCer-induced liver injury. α-GalCer injection also induced a marked increase in hepatic inducible NO synthase expression in C56BL/6 mice, but not in IRF-1 knockout mice. Inducible NO synthase knockout mice exhibited significantly reduced liver injury following α-GalCer treatment. Finally, we demonstrated that both NKT cells and hepatocytes expressed IRF-1 in response to α-GalCer. However, it appeared that the hepatocyte-derived IRF-1 was mainly responsible for α-GalCer-induced liver injury, based on the observation that inhibition of IRF-1 by RNA interference did not affect α-GalCer-induced NKT cell activation. Our findings revealed a novel mechanism of NKT cell-mediated liver injury in mice, which has implications in the development of human liver diseases.