Alcoholic liver diseases (ALD) affect over 10 million people in the world and costs more than $150 billion a year in USA. Long-term consumption of alcohol leads to various forms of liver injury including alcoholic hepatitis, fibrosis and cirrhosis, which are major causes of ALD-induced death. Ethanol (EtOH) induces various forms of cell death, which impacts the pathogenesis of ALD. Our preliminary results indicate that non-transcriptional Interferon regulatory factor 3 (Irf3) prevents ALD in mice. The ALD-preventive Irf3 mutant causes hepatocellular apoptosis during EtOH-exposure. Recently, we have uncovered a new Irf3-mediated apoptotic pathway in virus-infected cells. The apoptotic activity of Irf3 is not dependent on its function as a transcription factor. In this pathway, Irf3 is differentially activated to execute its apoptotic activity. Moreover, our preliminary results indicate that non-transcriptional Irf3 interacts with NF-?B signaling to inhibit pro-inflammatory gene expression. This led us to hypothesize that the Irf3-induced apoptotic cell death is related to its ALD-preventive function. To test our hypothesis, we have formulated two specific aims: a) investigate the specific cells in the liver that uses this pathway to prevent ALD and b) determine the biochemical mechanism of non-transcriptional Irf3-mediated apoptosis and inhibition of NF-?B activity. Successful completion of this study will elevate our knowledge on the prevention and treatment options for ALD. Based on our results, future studies will be directed to understand in-depth the molecular mechanism and specific modulators of this pathway to help prevent ALD.
Alcohol exposure causes major human health problems including various forms of alcoholic liver diseases (ALD). ALD affects millions of people worldwide and is a leading cause of preventable death (more than 30,000) in the US. Our results indicate that Interferon regulatory factor 3 (Irf3) prevents ALD in mice via a non- transcriptional activity. In this application, we proposed to investigate how Irf3 provides the protection against ALD. We have generated additional evidence that the ALD-protective function of Irf3 is associated with increase in apoptotic cell death, pre-dominantly of the hepatic non-parenchymal cells (NPCs). Our goal is to determine the hepatic cell types that undergo Irf3-dependent apoptosis and to dissect the biochemical mechanisms of Irf3-mediated protection of liver injury. Successful completion of the proposed work will reveal the molecular mechanisms leading to ALD progression and also future treatment options.
