Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice

J Hepatol. 2015 Oct;63(4):926-33. doi: 10.1016/j.jhep.2015.05.012. Epub 2015 May 27.


Background & aims: ER stress promotes liver fat accumulation and induction of inflammatory cytokines, which contribute to the development of steatohepatitis. Unresolved ER stress upregulates the pro-apoptotic CHOP. IL-1α is localized to the nucleus in apoptotic cells, but is released when these cells become necrotic and induce sterile inflammation. We investigated whether IL-1α is involved in ER stress-induced apoptosis and steatohepatitis.

Methods: We employed WT and IL-1α-deficient mice to study the role of IL-1α in ER stress-induced steatohepatitis.

Results: Liver CHOP mRNA was induced in a time dependent fashion in the atherogenic diet-induced steatohepatitis model, and was twofold lower in IL-1α deficient compared to WT mice. In the ER stress-driven steatohepatitis model, IL-1α deficiency decreased the elevation in serum ALT levels, the number of apoptotic cells (measured as caspase-3-positive hepatocytes), and the expression of IL-1β, IL-6, TNFα, and CHOP, with no effect on the degree of fatty liver formation. IL-1α was upregulated in ER-stressed-macrophages and the protein was localized to the nucleus. IL-1β mRNA and CHOP mRNA and protein levels were lower in ER-stressed-macrophages from IL-1α deficient compared to WT mice. ER stress induced the expression of IL-1α and IL-1β also in mouse primary hepatocytes. Recombinant IL-1α treatment in hepatocytes did not affect CHOP expression but upregulated both IL-1α and IL-1β mRNA levels.

Conclusion: We show that IL-1α is upregulated in response to ER stress and IL-1α deficiency reduces ER stress-induced CHOP expression, apoptosis and steatohepatitis. As a dual function cytokine, IL-1α may contribute to the induction of CHOP intracellularly, while IL-1α released from necrotic cells accelerates steatohepatitis via induction of inflammatory cytokines by neighboring cells.

Keywords: Apoptosis; CHOP; ER stress; IL-1α; Necrosis; Steatohepatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / genetics*
  • Gene Expression Regulation*
  • Interleukin-1alpha / biosynthesis
  • Interleukin-1alpha / deficiency*
  • Interleukin-1alpha / genetics
  • Liver Diseases / genetics*
  • Liver Diseases / metabolism
  • Liver Diseases / pathology
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger / genetics*
  • Real-Time Polymerase Chain Reaction
  • Transcription Factor CHOP / biosynthesis
  • Transcription Factor CHOP / genetics*


  • Ddit3 protein, mouse
  • Interleukin-1alpha
  • RNA, Messenger
  • Transcription Factor CHOP