Abstract
Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an anti-apoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.
Footnotes
Abbreviations: IL-24, interleukin 24; ER, endoplasmic reticulum; UPR, unfolded protein response; PERK, protein kinase RNA like ER kinase; IRE1, inositol-requiring enzyme 1; XBP1, X-box binding protein; ATF6, activating transcription factor 6; CHOP, transcription factor C/EBP homologous protein; GRP78, glucose-regulated protein 78; Tm, tunicamycin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRISPR/Cas9, clustered regularly interspersed short palindromic repeats / CRISPR associated protein 9; ISRIB, inhibitor of the integrated stress response AAV, adeno-associated virus; ALF, acute liver failure
Financial support statement: National Natural Science Foundation of China (81672801 to J.H., 81670598 to Q.X. and 81700498 to Haiyan Z.), Chen Guang Project in Shanghai Municipal Education Commission and Shanghai Education Development Foundation (15CG13 to J.H. and 17CG10 to Haiyan Z.) and National Key Research and Development Program of China (2016YFC0905901 to X.H.).