Interestingly, interferon-γ (IFN-γ) signaling is activated in patients and in the frequently utilized Tamoxifen rhesus rotavirus mouse model of BA, and is thought to play a key mechanistic role. Here we demonstrate intrahepatic biliary defects and up-regulated hepatic expression of IFN-γ pathway genes caused by genetic or pharmacological

inhibition of DNA methylation in zebrafish larvae. Biliary defects elicited by inhibition of DNA methylation were reversed by treatment with glucocorticoid, suggesting that the activation of inflammatory pathways was critical. DNA methylation was significantly reduced in bile duct cells from BA patients compared to patients with other infantile cholestatic disorders, thereby establishing a possible etiologic link between decreased DNA methylation, Selleckchem CP 868596 activation of IFN-γ signaling, and biliary defects in patients. Conclusion: Inhibition of DNA methylation leads to biliary defects and activation

of IFN-γ-responsive genes, thus sharing features with BA, which we determine to be associated with DNA hypomethylation. We propose epigenetic activation of IFN-γ signaling as a common etiologic mechanism of intrahepatic bile duct defects in BA. (HEPATOLOGY 2011;) Disorders of bile ducts range from infantile disorders such as biliary atresia and ductal plate abnormalities to conditions that affect older individuals such as primary sclerosing cholangitis, primary biliary cirrhosis, and cholangiocarcinoma. Fundamental to understanding all of these conditions is an understanding of the mechanisms of bile duct development. Bile ducts within the liver develop as hepatoblasts differentiate into hepatocytes and bile duct cells. In mammals, ducts develop as bile duct cells along the portal veins initially form plate-like

structures that coalesce into individual ducts.1 This process is governed by several transcription factors, including the onecut transcription factors hnf6 and onecut2, the homeodomain factor hnf1b, and members of the jagged/notch signaling pathway (reviewed2). Biliary atresia Verteporfin purchase (BA) is the most common identifiable cause of biliary disease in infants, but the etiology has remained elusive.3 Although both the rhesus rotavirus (RRV)-injected mouse model of BA and patients with BA demonstrate activation of interferon-γ (IFN-γ) and other inflammatory pathways,4, 5 efforts to identify associations with viral infections triggering this response in patients have been inconclusive. Interestingly, ewes and cows grazing on a Dysphania species that thrives during drought conditions in New South Wales gave birth to offspring with BA,6 supporting the role of an environmental toxin leading to BA, but no toxic exposures have been demonstrated in patients. There have been several reports of familial BA,7 but twin studies have been inconclusive,8-10 suggesting that a simple genetic cause of BA is unlikely.