Protein interactions were evaluated using immunoprecipitation. Results: Acute CCl4 administration to WT mice resulted in early activation of IRF3 and Type I IFNs, and was followed by hepatocyte death (increased serum ALT and activation of caspase-3 in the liver), as well as liver inflammation (increased TNF ). These events were accompanied by significant liver fibrosis upon repeated administration of CCl4 measured by increased -SMA and Sirius-red staining. Remarkably, mice deficient in IRF3 or STING showed no inflammation,

hepatocyte death or fibrosis after acute or chronic CCl4 selleck compound administration. Deficiency in TRAM or TRIF (IRF3 upstream activators) failed to protect from alcohol-induced hepatocyte death, liver fibrosis or inflammation suggesting the causal involvement of IRF3 and STING. These findings also demonstrated that hepatocyte death was required for liver fibrosis. We found that activated IRF3 was associated with STING and with the pro-apoptotic protein Bax and triggered the mitochondrial pathway of hepatocyte apoptosis. While IRF3 was essential, signaling BAY 73-4506 by IFNs via autocrine IFNAR receptor was not required suggesting that IRF3-driven apoptosis rather than IRF3-driven

Type I IFN production was responsible for hepatocyte death and CCl4-induced liver fibrosis. Conclusions: Our novel findings demonstrate that hepatocyte death is a pre-requisite for liver fibrosis. The CCl4-induced death of hepatocytes is mediated by the interaction between the ER adaptor protein, STING, and IRF3, resulting in activation of the mitochondrial pathway of hepatocyte death. Thus, liver damage and hepatocyte death likely represent a permissive initial event for liver fibrogenesis. Disclosures: Gyongyi Szabo – Consulting: Idenix; Grant/Research Support: BMS, GSK, Conatus, Idera, Johnson&Johnson, Novartis, Ocera, Roche, Shering – Plough, Wyeth, Integrated Carnitine palmitoyltransferase II Therapeutics, Idera The following people have nothing to disclose: Arvin Iracheta-Vellve, Jan

Pet-rasek, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald Propose of study: Alcohol acts through numerous pathways to lead to the development of alcoholic liver disease (ALD). CYP2E1 is the major component of the microsomal ethanol-oxidizing enzyme that produces reactive oxygen species (ROS) leading to membrane lipid peroxidation and cell toxicity. CYP2E1 is inducible by ethanol and it is primarily due to a post-translational mechanism that protects the enzyme from degradation. However, transcriptional mechanisms may also contribute. Sumoylation is a posttranslational modification able to modify the activity, localization, and expression of the target protein by a covalent bond where small ubiquitin modifier (SUMO) is a tag.