Department of Medicine, Division of Gastroenterology; Department of Medicine, Division of Infectious Diseases and Immunology
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
Cell Biology | Digestive System Diseases | Gastroenterology | Genomics | Hepatology | Immunopathology
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.
steatohepatitis, Kupffer cells, stimulator of interferon genes, interferon regulatory factor 3
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DOI of Published Version
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
Proceedings of the National Academy of Sciences of the United States of America
Petrasek, Jan; Iracheta-Vellve, Arvin; Csak, Timea; Satishchandran, Abhishek; Kodys, Karen; Kurt-Jones, Evelyn A.; Fitzgerald, Katherine A.; and Szabo, Gyongyi, "STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease" (2013). Gastroenterology Publications and Presentations. 136.