title: Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Kandel-Kfir
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Almog
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Aviv
authors.initials: A
authors.lastname: Shaish
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Gadi
authors.initials: G
authors.lastname: Shlomai
authors.affiliation: The Pathology Department, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Anafi
authors.affiliation: The Pathology Department, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Camila
authors.initials: C
authors.lastname: Avivi
authors.affiliation: The Pathology Department, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Itamar
authors.initials: I
authors.lastname: Grosskopf
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
authors.affiliation: The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Israel. Electronic address: yehuda.kamari@sheba.health.gov.il.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Kamari
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005786:Gene Expression Regulation; D053582:Interleukin-1alpha / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C497250:Ddit3 protein, mouse; D053582:Interleukin-1alpha; D012333:RNA, Messenger; D051742:Transcription Factor CHOP
keywords: Apoptosis; CHOP; ER stress; IL-1α; Necrosis; Steatohepatitis