Mini review
Regulation of hepatocyte fate by interferon-γ

https://doi.org/10.1016/j.cytogfr.2011.01.001Get rights and content

Abstract

Interferon (IFN)-γ is a cytokine known for its immunomodulatory and anti-proliferative action. In the liver, IFN-γ can induce hepatocyte apoptosis or inhibit hepatocyte cell cycle progression. This article reviews recent mechanistic reports that describe how IFN-γ may direct the fate of hepatocytes either towards apoptosis or a cell cycle arrest. This review also describes a probable role for IFN-γ in modulating hepatocyte fate during liver regeneration, transplantation, hepatitis, fibrosis and hepatocellular carcinoma, and highlights promising areas of research that may lead to the development of IFN-γ as a therapy to enhance recovery from liver disease.

Introduction

Interferon (IFN)-γ is an inflammatory cytokine recognized for its antiviral and immunomodulatory properties. Also known as type II interferon, IFN-γ is secreted primarily by activated T cells and natural killer (NK) cells [1]. In the liver, the action of IFN-γ extends beyond immune modulation to include regulation of hepatocyte apoptosis and cell cycle progression during liver disease [2], [3]. In light of the growing understanding of IFN-γ as a contributing factor to liver disease, it is intriguing to consider emerging therapeutic approaches that modulate IFN-γ signaling. This review aims to illuminate how IFN-γ regulates hepatocyte apoptosis and cell cycle progression and explore the multifaceted role of IFN-γ during liver disease.

Section snippets

Hepatic sources and targets of IFN-γ

The liver parenchyma is comprised of hepatocytes, which are fully differentiated, metabolically active cells. Under normal conditions, hepatocytes are mitotically quiescent, yet they can be induced to replicate following injury due to toxicant exposure, viral infection, or following surgical resection of a substantial portion of the liver [4]. Hepatocytes themselves are not substantial producers of IFN-γ. Instead, IFN-γ production is attributed to activated lymphocytes, such as NK cells, T

IFN-γ signaling pathways

The IFN-γ receptor is a transmembrane, heterodimeric protein comprised of a constitutively expressed alpha chain (IFNGR1), which contains a ligand-binding domain and an inducible, non-ligand-binding beta chain (IFNGR2) [10]. The biologically active IFN-γ dimer interacts with IFNGR1, which initiates the association of IFNGR1 with IFNGR2 and subsequent phosphorylation of JAK1 and JAK2 kinases (Fig. 1). Activated JAK kinases phosphorylate the cytoplasmic tails of IFNGR1 subunits, providing a

IFN-γ induces hepatocyte apoptosis

IFN-γ elicits apoptosis in numerous cell types, including hepatocytes, through mechanisms that are poorly understood and likely to involve multiple pathways [2], [21]. In primary mouse hepatocytes, IFN-γ treatment induces apoptosis through a p53-independent, IRF-1-dependent mechanism that requires de novo protein synthesis [2], [22]. As a well-established tumor suppressor, IRF-1 is implicated in cell growth control, oncogene transformation and apoptosis [23]. IRF-1 is primarily regulated at the

IFN-γ inhibits hepatocyte cell cycle progression

IFN-γ inhibits the proliferation of freshly isolated hepatocytes [2] and some hepatocyte-derived cell lines [51], [52]. In primary mouse hepatocytes, IFN-γ treatment inhibits DNA synthesis through a G1 cell cycle arrest that requires both Stat1 and the tumor suppressor protein, p53 [2], [53]. This G1 arrest coincides with increased expression the G1 cyclin-dependent kinase inhibitor, p21 [2]. As transcription factors, p53 and Stat1 proteins can individually activate the p21 promoter in response

IFN-γ and liver regeneration

Liver regeneration is a multistep process in which normally quiescent hepatocytes proliferate to replace damaged or lost liver mass due to widespread injury or partial surgical resection [59]. During liver regeneration following 70% partial hepatectomy (PH), hepatocytes proliferate in response to cytokine and growth factor signals that are largely provided by nonparenchymal cells in the liver [60]. Understanding mechanisms of liver regeneration is complicated by the existence of interconnected

Conclusion

In the liver, hepatocyte proliferation is essential for recovery after surgical resection or transplantation, whereas hepatocyte apoptosis is crucial for maintaining organ size and preventing uncontrolled proliferation, such as occurs during hepatocellular carcinoma. A growing body of evidence demonstrates that IFN-γ has anti-proliferative consequences on hepatocytes by stimulating apoptosis or eliciting a cell cycle arrest. The mechanisms by which IFN-γ orchestrates hepatocyte fate appear to

Acknowledgement

This work was supported by National Institutes of Health grants P20RR016454 from the INBRE Program of the National Center for Research Resources and R15DK088749 from the National Institute of Diabetes and Digestive and Kidney Diseases.

Christopher J. Horras is a graduate student in the Department of Biological Sciences at Boise State University. He holds a B.S. in Biology from the College of Idaho and a M.A. in teaching from The University of Portland. His research interests lie in understanding how the innate immune system regulates liver regeneration.

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    • Cited by (0)

    Christopher J. Horras is a graduate student in the Department of Biological Sciences at Boise State University. He holds a B.S. in Biology from the College of Idaho and a M.A. in teaching from The University of Portland. His research interests lie in understanding how the innate immune system regulates liver regeneration.

    Cheri L. Lamb is a graduate student in the Department of Biological Sciences at Boise State University, where she also earned a B.S. in health sciences. Her research interests include understanding how exposure to aryl hydrocarbon receptor ligands modulates Stat1 activation in response to IFN-γ-treatment.

    Kristen A. Mitchell, PhD, is an assistant professor in the Department of Biological Sciences at Boise State University. She received her Ph.D. in Pharmacology and Toxicology from Washington State University (Laboratory of Dr. B. Paige Lawrence) and completed postdoctoral training at the University of Texas Medical Branch in Galveston (Laboratory of Dr. Cornelis Elferink). Her research interests include investigating how the aryl hydrocarbon receptor regulates cell cycle progression and how exogenous ligands for this receptor cause immunotoxicity and elicit a cell cycle arrest. She holds memberships in the American Physiological Society and the Society of Toxicology.

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