Interferon regulatory factor-1 activates autophagy to aggravate hepatic ischemia-reperfusion injury via the P38/P62 pathway in mice

• DOI: 10.1038/srep43684
• Publication Date: 2017-03-07T10:51:25Z
• Authors: Yao Yu; Shipeng Li; Zhen Wang; Jindan He; Yijie Ding; Haiming Zhang; Wenli Yu; Yiwei Shi; Zilin Cui; Ximo Wang; Zhiliang Wang; Liying Sun; Rongxin Zhang; Hongyin Du; Zhijun Zhu
• Keywords: Mice, Knockout; 0303 health sciences; Liver Diseases; Gene Expression; Models, Biological; p38 Mitogen-Activated Protein Kinases; Article; Cell Line; Disease Models, Animal; Mice; 03 medical and health sciences; Liver; Reperfusion Injury; Sequestosome-1 Protein; Autophagy; Hepatocytes; Animals; Genetic Predisposition to Disease; Interferon Regulatory Factor-1; Signal Transduction

AbstractIncreasing evidence has linked autophagy to a detrimental role in hepatic ischemia- reperfusion (IR) injury (IRI). Here we focus on the role of interferon regulatory factor-1 (IRF-1) in regulating autophagy to aggravate hepatic IRI. We found that IRF-1 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling. This increased IRF-1 expression, which was allied with high autophagic activity, amplified liver damage to IR, an effect which was abrogated by IRF-1 depletion. Moreover, IRF-1 contributed to P38 induced autophagic and apoptotic cell death, that can play a key role in liver dysfunction. The levels of P62 mRNA and protein were increased when P38 was activated and decreased when P38 was inhibited by SB203580. We conclude that IRF-1 functioned as a trigger to activate autophagy via P38 activation and that P62 was required for this P38-mediated autophagy. IRF-1 appears to exert a pivotal role in hepatic IRI, by predisposing hepatocytes to activate an autophagic pathway. Such an effect promotes autophagic cell death through the P38/P62 pathway. The identification of this novel pathway, that links expression levels of IRF-1 with autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.