title: A critical role for IFN regulatory factor 1 in NKT cell-mediated liver injury induced by alpha-galactosylceramide.
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 hepatocytes expressed IRF-1 in response to alpha-GalCer. However, it appeared that the hepatocyte-derived IRF-1 was mainly responsible for alpha-GalCer-induced liver injury, based on the observation that inhibition of IRF-1 by RNA interference did not affect alpha-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.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Zongxian
authors.initials: Z
authors.lastname: Cao
authors.forename: Rajeev
authors.initials: R
authors.lastname: Dhupar
authors.forename: Changchun
authors.initials: C
authors.lastname: Cai
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Li
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: David A
authors.initials: DA
authors.lastname: Geller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000008:administration & dosage / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D005699:Galactosylceramides; D050856:Interferon Regulatory Factor-1; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II