UMMS Affiliation

Department of Medicine, Division of Gastroenterology; Department of Medicine, Division of Infectious Diseases and Immunology

Date

10-8-2013

Document Type

Article

Medical Subject Headings

Animals; Apoptosis; Endoplasmic Reticulum Stress; Hepatocytes; Immunity, Innate; Interferon Regulatory Factor-3; Liver; Liver Diseases, Alcoholic; Membrane Proteins; Mice; Mice, Knockout; Phosphorylation; Regression Analysis; Signal Transduction; Triglycerides

Disciplines

Cell Biology | Digestive System Diseases | Gastroenterology | Genomics | Hepatology | Immunopathology

Abstract

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of STING prevented IRF3 phosphorylation by ethanol or ER stress, and absence of IRF3 prevented hepatocyte apoptosis. The pathogenic role of IRF3 in ALD was independent of inflammation or Type-I interferons. Thus, STING and IRF3 are key determinants of ALD, linking ER stress signaling with the mitochondrial pathway of hepatocyte apoptosis.

Rights and Permissions

Citation: Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16544-9. doi: 10.1073/pnas.1308331110 Link to article on publisher's site

Comments

Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.

Related Resources

Link to Article in PubMed

Keywords

steatohepatitis, Kupffer cells, stimulator of interferon genes, interferon regulatory factor 3

PubMed ID

24052526

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