The Effect Of IL-24 In Endoplasmic Reticulum Stress-related Liver Injury And Its Predictive Role On The Prognosis Of Hepatocellular Carcinoma

OBJECTIVE:Interleukin-24（IL-24）was first identified as a negative regulator of human melanocytes and involved in terminal differentiation.It has a suppression role on a variety of malignant tumor cells and is associated with ER stress-mediated cell death.However,its expression and function in hepatocytes remains unclear.Endoplasmic reticulum（ER）stress is associated with liver damage caused by various causes.There are adequate evidences show that the PERK-e IF2α-CHOP pathway in ER stress is important in the development of acute liver injury and promotes cell apoptosis.In this study,we aimed to elucidate the role and mechanism of IL-24 in ER stress-mediated hepatocyte death.Methods:1.We establish the acute liver injury model by treat 8-week-old female C57BL/6wild-type or IL-24 knockout（KO）mice with carbon tetrachloride（CCl4）or acetaminophen;2.We use tunicamycin to stimulate normal mouse hepatocytes with IL-24 knockout or overexpression;3.To evaluate IL-24 and ER stress-related proteins in healthy liver transplant donors or patients with acute liver failure.Western blot,q RT-PCR and immunohistochemistry（IHC）were employed to identify the regulation of IL-24 and related signaling pathways.RESULTS:IL-24 expression in hepatocytes increased transiently in acute liver injury associated with ER stress.Deletion of hepatocyte IL-24 aggravate acute liver injury induced by CCL₄ or APAP and Tm-induced hepatocyte death.Moreover,hepatocyte IL-24 can alleviate liver damage by inhibiting the sustained activation of the PERK-e IF2α-CHOP pathway.In addition,it has been found that patients with acute liver failure show a significant decrease in liver IL-24 expression,which is inversely correlated with disease progression.In addition,patients with high IL-24 expression in HCC tissue had better prognosis.CONCLUSION:Hepatocyte ER stress induces IL-24 regulation,while hepatocyte IL-24inhibits PERK-e IF2αbranch activation,maintains ER homeostasis and reduces CHOP-mediated cell death.In addition,IL-24 can be an predictor of postoperative outcome in HCC patients.