Glycogen synthase kinase-3 facilitates con a-induced IFN-γ-mediated immune hepatic injury

Cheng-Chieh Tsai, Wei-Ching Huang, Chia-Ling Chen, Chia-Yuan Hsieh, Yee-Shin Lin, Shun-Hua Chen, Kao-Chi Yang, Chiou Feng Lin

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5 Citations (Scopus)

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-γsignaling. 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.

Original languageEnglish
Pages (from-to)3867-3877
Number of pages11
JournalJournal of Immunology
Volume187
Issue number7
DOIs
Publication statusPublished - Oct 1 2011

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ASJC Scopus subject areas

  • Immunology

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