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Role of Glycogen Synthase Kinase-3 in Interferon-γ-Mediated Immune Hepatitis - PubMed

  • ️Sat Jan 01 2022

Review

Role of Glycogen Synthase Kinase-3 in Interferon-γ-Mediated Immune Hepatitis

Chia-Ling Chen et al. Int J Mol Sci. 2022.

Abstract

Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a vital glycogen synthase regulator controlling glycogen synthesis, glucose metabolism, and insulin signaling. GSK-3 is widely expressed in different types of cells, and its abundant roles in cellular bioregulation have been speculated. Abnormal GSK-3 activation and inactivation may affect its original bioactivity. Moreover, active and inactive GSK-3 can regulate several cytosolic factors and modulate their diverse cellular functional roles. Studies in experimental liver disease models have illustrated the possible pathological role of GSK-3 in facilitating acute hepatic injury. Pharmacologically targeting GSK-3 is therefore suggested as a therapeutic strategy for liver protection. Furthermore, while the signaling transduction of GSK-3 facilitates proinflammatory interferon (IFN)-γ in vitro and in vivo, the blockade of GSK-3 can be protective, as shown by an IFN-γ-induced immune hepatitis model. In this study, we explored the possible regulation of GSK-3 and the potential relevance of GSK-3 blockade in IFN-γ-mediated immune hepatitis.

Keywords: glycogen synthase kinase-3; immune hepatitis; interferon-γ; liver.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

The various roles of GSK-3 contribute to diverse bioactivities and human diseases.

Figure 2
Figure 2

Molecular regulation of GSK-3 for activating the diverse intracellular factors.

Figure 3
Figure 3

The involvement of GSK-3 in IFN-γ signaling.

Figure 4
Figure 4

A hypothetical model for GSK-3-facilitated IFN-γ immune hepatitis. Treatment of ConA causes immune hepatitis through a mechanism involving NKT activation, hepatic cell apoptosis, and inflammatory activation. In activated NKT cells, in addition to CD95L induction, ConA induces GSK-3 activation to facilitate T-bet-modulated IFN-γ generation. Furthermore, signaling of IFN-γ and its receptor IFNGR may cause GSK-3-regulated Jak2/STAT1 signaling in hepatocytes to facilitate IFN-γ-activated Jak2-STAT1 signaling. IFN-γ is essential for inducing hepatic injury, including CD95-mediated hepatic cell death and hepatic inflammatory responses such as iNOS/NO biosynthesis, CD54 induction, and immune T cell and granulocyte infiltration. These findings illustrate a pathogenic role of GSK-3 in guiding ConA-induced immune hepatitis by facilitating IFN-γ expression, signaling, hepatic injury, and inflammation.

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