Interferon Regulatory Factor-1 (IRF1) activates autophagy to promote liver ischemia/reperfusion injury by inhibiting β-catenin in mice.

Bing Yan,Qiang Du,Patricia Loughran,Donna B. Stolz,Christof Kaltenmeier,Yihe Yan,David A. Geller,Xiao Cui,Jing Luo,Partha Mukhopadhyay

doi:10.1371/journal.pone.0239119

Abstract

Autophagy is an important factor in liver ischemia-reperfusion injury. In the current study we investigate the function of interferon regulatory factor-1 (IRF1) in regulating autophagy to promote hepatic ischemia reperfusion injury (IR). The high expression of IRF1 during hepatic IR exhibited increased liver damage and was associated with activation of autophagy shown by Western blot markers, as well as immunofluorescent staining for autophagosomes. These effects were diminished by IRF1 deficiency in IRF1 knock out (KO) mice. Moreover, the autophagy inhibitor 3-MA decreased IR-induced liver necrosis and markedly abrogated the rise in liver injury tests (AST/ALT). β-catenin expression decreased during liver IR and was increased in the IRF1 KO mice. Immunoprecipitation assay showed the binding between IRF1 and β-catenin. Overexpression of IRF1 induced autophagy and also inhibited the expression of β-catenin. β-catenin inhibitor increased autophagy while β-catenin agonist suppressed autophagy in primary mouse hepatocytes. These results indicate that IRF1 induced autophagy aggravates hepatic IR injury in part by inhibiting β-catenin and suggests that targeting IRF1 may be an effective strategy in reducing hepatic IR injury.

Highlights

Liver ischemia-reperfusion injury (IR) is involved in hypoxic liver organ stress followed by reperfusion injury after re-oxygenation [1, 2]
To test the effects of interferon regulatory factor-1 (IRF1) on hepatocyte growth, isolated mouse hepatocytes from wild type (WT) or IRF1 knock out (KO) mice were exposed to 1% hypoxia for 1 hour, re-oxygenated
The major findings of this study are: (i) IRF1 was induced in hepatic IR injury; (ii) IRF1 activity induced autophagy during liver warm IR; (iii) IRF1 bound β-catenin protein and IRF1

Summary

Introduction

Liver ischemia-reperfusion injury (IR) is involved in hypoxic liver organ stress followed by reperfusion injury after re-oxygenation [1, 2]. Hepatic IR causes liver dysfunction postoperatively and is seen after liver resection or liver transplantation [3,4,5]. Studying the early signaling events accounting for liver damage associated with IR may provide strategies to mitigate liver injury. Autophagy is an intracellular process where impaired proteins or organelles are phagocytosed and transported to lysosomes for degradation [6]. Low level autophagy helps cells to satisfy energy demands in periods that include hypoxia [7].

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Results

Conclusion