Disclosures: The following people have nothing to disclose: Christy E. Trussoni, Patrick L. Splinter, James H. Tabibian, Steven P. O’Hara The secretin dependent biliary secretion of ions and water by transporters and/or channels is essential for the regulation of biliary flow. The cystic fibrosis transmembrane conductance regulator (CFTR) see more plays a key role in the chloride secretion into the bile. In the cystic fibrosis (CF) patients, totally 5 to 10% of patients develop the progressive biliary fibrosis resembling primary sclerosing cholangitis. The loss of CFTR in mice also leads to the liver failure. ERM (ezrin-radixin-moesin)

proteins are identified as cross-linkers between plasma membrane proteins and actin cytoskeleton. Ezrin interacts with Na+/ H+ exchanger regulatory factor-1 (NHERF1) via its N-terminal

binding domain and with actin cytoskeleton via its C-terminal actin-binding domain. CFTR is associated with NHERF1 via its c-terminal PDZ binding motif. In the liver, ezrin, but not radixin or moesin, is exclusively expressed in the cholangiocytes and colocalizes with CFTR and NHERF1 at apical membrane of cholangiocyte. In the STI571 chemical structure present study, we have found that ezrin knockdown (Vil2kd/kd) mice develop severe hepatic failure characterized by extensive bile duct proliferation, periductular fibrosis, and intrahepatic bile acid accumulation. In these mice, apical membrane localizations of CFTR and NHERF1 were disturbed in the bile ducts. Stable expression of a dominant negative form of ezrin in immortalized mouse cholangiocytes also led to the reduction of the surface expression of CFTR. Furthermore, the surface expressions of other transport proteins, which are required for the apical ion and water transport in bile duct including Anion exchanger 2 (AE-2) and aquaporin 1 (AQP1), were also disturbed in Florfenicol cholangiocytes.

Reduced surface expression of these transport proteins was accompanied by reduced CFTR-mediated Cl- efflux activity. These data suggest that dysfunction of ezrin mimics important aspects of the pathological mechanisms responsible for cholangiopathies via the regulation of apical membrane transport in bile ducts. Disclosures: The following people have nothing to disclose: Ryo Hatano, Kaori Akiyama, Shinji Asano Background. Cholangiocytes release a variety of inflammatory mediators in response to injury. Cholangiocyte release of IL-6 is of particular importance, since it is necessary for liver regeneration. However, the mechanisms regulating IL-6 in cholangiocytes are largely unknown. Since adenosine is increasingly recognized as a potent mediator of liver injury, we tested the hypothesis that extracellular adenosine induces upregulation of IL-6 in cholangiocytes in a physiologically relevant fashion. Specific Aims.