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

The Journal of Immunology : Official Journal of the American Association of Immunologists
Zongxian CaoDavid A Geller

Abstract

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 alpha-galactosylceramide (alpha-GalCer) causes liver injury through mechanisms that are not well understood. We undertook studies to characterize the key pathways involved in alpha-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 alpha-GalCer treatment. Neutralization of either TNF-alpha or IFN-gamma inhibited alpha-GalCer-mediated IRF-1 upregulation. alpha-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 alpha-GalCer-induced liver injury. alpha-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 alpha-GalCer treatment. Finally, we demonstrated that both NKT cells and hepatocyte...Continue Reading

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Citations

Nov 10, 2013·The Journal of Clinical Investigation·Martin K ThomsenErwin F Wagner
Oct 12, 2018·American Journal of Physiology. Gastrointestinal and Liver Physiology·John Robert KluneDavid A Geller
May 13, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Shinichiro YokotaDavid A Geller
Jan 23, 2014·European Journal of Immunology·Meenakshi SubramanianAkio Ohta
Apr 8, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Dimitra VyrlaAristides G Eliopoulos
Feb 20, 2020·Seminars in Cancer Biology·Cristina FloreanMarc Diederich

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