In this application, we design experiments aimed to exploit the recent discovery and in our laboratories that interleukin-6(IL-6) is a complete mitogen for human biliary epithelium IL-6 also, is elevated in vivo, in human liver diseases where biliary epithelial cell proliferation is seen, such as alcoholic liver disease and fulminant failure. IL-6 also is a major regulatory protein for hepatocyte growth factor (HGF) and c-met receptor production, which is another complete bile duct cell mitogen. The direct and indirect role of IL-6 in inflammatory liver diseases where prolonged biliary epithelial proliferation play an important role will be investigated by: 1. Use of in vitro cultures of human bile duct epithelium and diseased human liver tissue: We have ready access to normal and diseased human liver tissue from the largest liver transplant center in the world. Approximately 350 diseased livers and normal liver tissue from 30 other cases are available each year. Using these resources we will: A. Characterize in vitro, the effect of lL-6 and two key pro-inflammatory cytokines (IL-1beta on TNF alpha) on human bile duct epithelium responsiveness to HGF and IL-6 and on production of matrix proteins. B. Characterize in vivo, the microenvironment of human livers disease associated and IL-6 elevators where bile ductular proliferation plays an important role ( submassive necrosis and alcoholic liver disease). 2. Use of IL-6 """"""""knockout"""""""" mice and IL-6 transgenic mice: Through collaborations with I. Campbell of Scripps Institute and Clinic and V. Poli, Ph.D., from the Molecular Biology Institute in Rome, Italy, we have available to us mice that over-express IL-6 (transgenics) and mice that are incapable of IL-6 production (knockout), respectively. Using these animals we will: A. Evaluate in vivo, the role of IL-6 in biliary epithelial growth after stimuli that cause bile duct proliferation. B. Use IL-6 antagonists, such as anti-IL6 monoclonal antibodies, suramin or inhibitors of intracellular second signaling molecules to determine if such interventions could have therapeutic implications for patients.
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