Interferon-Gamma Directly Mediates Developmental Biliary Defects

Abstract

Biliary atresia (BA) is the most common identifiable hepatobiliary disease affecting infants, in which there are defects in intra-and extrahepatic bile ducts and progressive fibrosis. Activation of interferon-gamma (IFNc) appears to be critical in both patients with BA and in rodent models of BA. We have recently reported a zebrafish model of biliary disease that shares features with BA, in which inhibition of DNA methylation leads to intrahepatic biliary defects and activation of IFNc target genes. Here we report that ifng genes are hypomethylated and upregulated in zebrafish larvae treated with azacytidine (azaC), an inhibitor of DNA methylation. Injection of IFNc protein into developing zebrafish larvae leads to biliary defects, suggesting that activation of the IFNc pathway is sufficient to cause developmental biliary defects. These defects are associated with decreased cholangiocyte proliferation and with a decrease in the expression of vhnf1 (hnf1b, tcf2), which encodes a homeodomain protein with previously reported roles in biliary development in multiple models. These results support an importance of IFNc in mediating biliary defects, and also demonstrate the feasibility of direct injection of intact protein into developing zebrafish larvae.

Zebrafish: An Important Tool for Liver Disease Research

“…53 Moreover, DNA hypomethylation in zebrafish induced the interferon gamma signaling pathway, and injecting zebrafish larvae with interferon gamma recapitulated the biliary defects mimicking biliary atresia. 54 This provides a potential pathogenic mechanism for biliary atresia which has been proposed in some pediatric cases to be caused by a viral agent that may trigger an antiviral immune response that destroys the developing biliary tract. 55,56 The hypothesis that an antiviral immune response might cause biliary atresia is supported by the finding that corticosteroids prevent the biliary defect caused by DNA hypomethylation in zebrafish, 53 suggesting that these drugs might be used to treat patients with biliary atresia.…”

Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis

“…Relying solely on mechanism-based markers is complicated by the fact that most cases of drug-induced hepatotoxicity are idiosyncratic, and only 30% of instances correlate with cause in the national registry (Alfirevic and Pirmohamed, 2012). Further, phenotypic linking of gene expression signatures could identify novel molecular mechanisms linked to drug-induced toxicity and improve the fidelity of biomarker-based diagnostic assays (Cui et al, 2013).…”

The lure of zebrafish in liver research: regulation of hepatic growth in development and regeneration

“…Early studies by Farooq et al found that the HDAC inhibitor valproic acid impaired liver development by inhibiting hepatoblast specification and differentiation[71]. Embryonic exposure to 5-azacytidine has a deleterious effect on biliary development due to DNA hypomethylation and stimulation of an interferon-γ mediated inflammatory response[72,73]. Recent work using the mTORC inhibitors Torin1 or rapamycin have revealed a critical role for mTOR signaling in Wnt-mediated liver hyperplasia[74].…”