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

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-1 alpha is localized to the nucleus in apoptotic cells, but is released when these cells become necrotic and induce sterile inflammation. We investigated whether IL-1 alpha is involved in ER stress-induced apoptosis and steatohepatitis. Methods: We employed WT and IL-1 alpha-deficient mice to study the role of IL-1 alpha 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-1 alpha deficient compared to WT mice. In the ER stress-driven steatohepatitis model, IL-1 alpha deficiency decreased the elevation in serum ALT levels, the number of apoptotic cells (measured as caspase-3-positive hepatocytes), and the expression of IL-1 beta, IL-6, TNF alpha, and CHOP, with no effect on the degree of fatty liver formation. IL-1 alpha was upregulated in ER-stressed-macrophages and the protein was localized to the nucleus. IL-1 beta mRNA and CHOP mRNA and protein levels were lower in ER-stressed-macrophages from IL-1 alpha deficient compared to WT mice. ER stress induced the expression of IL-1 alpha and IL-1 beta also in mouse primary hepatocytes. Recombinant IL-1 alpha treatment in hepatocytes did not affect CHOP expression but upregulated both IL-1 alpha and IL-1 beta mRNA levels. Conclusion: We show that IL-1 alpha is upregulated in response to ER stress and IL-1 alpha Z deficiency reduces ER stress-induced CHOP expression, apoptosis and steatohepatitis. As a dual function cytokine, IL-1 alpha may contribute to the induction of CHOP intracellularly, while IL-1 alpha released from necrotic cells accelerates steatohepatitis via induction of inflammatory cytokines by neighboring cells. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.