Viral infections of the liver are common and affect life quality and expectancy. It is estimated that over 2 billion people worldwide are infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). Both viruses can cause chronic inflammation of the liver, tissue damage and hepatocellular carcinoma. Approximately 650,000 people die each year due to infections with HBV or HCV. Our long-term goals are to elucidate molecular mechanisms regulating inflammation, identify defective pathways in diseases and use this knowledge to develop novel therapies. Interleukin-1 (IL-1) is a pleiotropic cytokine that initiates many of the immunological responses to infections and tissue damage, including local inflammation and systemic acute phase responses. IL-1 stimulates cellular responses through activation of intracellular signaling pathways leading to stabilization of certain mRNAs and increased transcription mediated by factors such as AP-1, NF-kB and STAT3. The signaling pathways are shared by the pathogen recognizing Toll-like receptors and involve IL-1 receptor associated kinase-1 (IRAK1). Rapid degradation of IRAK1 following cell stimulation appears to provide a molecular brake on inflammation and inadequately regulated IRAK1 may play an important role in chronic inflammation. The Pellino proteins Pellino1 and Pellino2 represent a novel group of proteins, which appear to be involved in Toll/IL-1 signal transduction. However, their functions are largely unknown. We have previously identified a novel Pellino protein, Pellino3. Our previous studies have demonstrated that Pellino proteins are involved in IL-1 signaling and interact with several signaling molecules, including IRAK1. New data suggest that Pellino proteins regulate post-transcriptional modification and activity of IRAK1. Preliminary analyses also indicate that Pellino1 is the predominant form in hepatocytes and expression of Pellino1 is down-regulated in liver tissue from patients infected with HBV or HCV. This expression pattern appears to be specific to liver tissue and viral infections of the liver. Hepatocytes with reduced Pellino1 levels have a diminished capacity to produce IL-8. We hypothesize that down-regulation of Pellino1 facilitates diminished inflammatory responses of hepatocytes. A novel Pellino1 knockout mouse strain will be characterized and evaluated as a model in which our hypothesis can be tested and liver disease studied. Expression of Pellino1 during human HBV and HCV infections will be determined. Through siRNA mediated knockdown of Pellino1 mRNA Pellino1 dependent gene expression in human hepatocytes will be defined using genomewide microarray expression profiling. These studies will significantly improve our understanding of the involvement of Pellino1 in liver inflammation. The project will further set the stage for future exploration of the role of IL-1, Pellino1 and hepatocytes in liver disease and disease outcomes.
Viral infections of the liver causing liver inflammation (hepatitis) and cancer are common and affect life quality and expectancy. This project will elucidate molecular mechanisms regulating inflammation, specifically identifying defective pathways in diseases and using this knowledge to develop new therapies for both hepatitis B and hepatitis C and explore molecular mechanisms involved in regulating pro-inflammatory interleukin-1 signal transduction in liver cells. An improved understanding of liver inflammation and the associated molecular pathways may facilitate the development of novel therapies for hepatitis and liver cancer.
