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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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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Glycogen Synthase Kinase 3
Liver
Wounds and Injuries
Inbred C57BL Mouse
Hepatocytes
Cell Death
Transcription Factors
Apoptosis
Inflammation
Natural Killer T-Cells
Fas Ligand Protein
Granulocytes
Nitric Oxide Synthase
Necrosis
Up-Regulation
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology

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Glycogen synthase kinase-3 facilitates con a-induced IFN-γ-mediated immune hepatic injury. / Tsai, Cheng-Chieh; Huang, Wei-Ching; Chen, Chia-Ling; Hsieh, Chia-Yuan; Lin, Yee-Shin; Chen, Shun-Hua; Yang, Kao-Chi; Lin, Chiou Feng.

In: Journal of Immunology, Vol. 187, No. 7, 01.10.2011, p. 3867-3877.

Research output: Contribution to journalArticle

Tsai, Cheng-Chieh ; Huang, Wei-Ching ; Chen, Chia-Ling ; Hsieh, Chia-Yuan ; Lin, Yee-Shin ; Chen, Shun-Hua ; Yang, Kao-Chi ; Lin, Chiou Feng. / Glycogen synthase kinase-3 facilitates con a-induced IFN-γ-mediated immune hepatic injury. In: Journal of Immunology. 2011 ; Vol. 187, No. 7. pp. 3867-3877.
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