title: Glycogen synthase kinase-3 facilitates con a-induced IFN-γ-- mediated immune hepatic injury.
abstract: Immune hepatic injury induced by Con A results primarily from IFN-γ-mediated inflammation, followed by hepatic cell death. Glycogen synthase kinase (GSK)-3, which acts proapoptotically and is proinflammatory, is also important for facilitating IFN-γ signaling. We hypothesized a pathogenic role for GSK-3 in Con A hepatic injury. Con A stimulation caused GSK-3 activation in the livers of C57BL/6 mice. Inhibiting GSK-3 reduced Con A hepatic injury, including hepatic necrosis and apoptosis, inflammation, infiltration of T cells and granulocytes, and deregulated expression of adhesion molecule CD54. Con A induced hepatic injury in an IFN-γ receptor 1-dependent manner. Con A/IFN-γ induced activation and expression of STAT1 in a GSK-3-dependent manner. GSK-3 facilitated IFN-γ-induced inducible NO synthase, but had limited effects on CD95 upregulation and CD95-mediated hepatocyte apoptosis in vitro. Notably, inhibiting GSK-3 decreased Con A-induced IFN-γ production in both wild-type and IFN-γ receptor 1-deficient C57BL/6 mice. In Con A-activated NKT cells, GSK-3 was also activated and was required for nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-γ, but it was not required for CD95 ligand expression or activation-induced cell death. These results demonstrate the dual and indispensable role of GSK-3 in Con A hepatic injury by facilitating IFN-γ-induced hepatopathy.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 701, Taiwan.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Tsai
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Huang
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.forename: Chia-Yuan
authors.initials: CY
authors.lastname: Hsieh
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
authors.forename: Shun-Hua
authors.initials: SH
authors.lastname: Chen
authors.forename: Kao-Chi
authors.initials: KC
authors.lastname: Yang
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002469:Cell Separation; D003208:Concanavalin A / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000276:immunology / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008934:Mitogens / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D008934:Mitogens; D003208:Concanavalin A; D007371:Interferon-gamma; D038362:Glycogen Synthase Kinase 3