IFN-gamma inhibits hepatic progenitor cell activation in chronic liver damage

Abstract

Background & Aims: Hepatic progenitor cells (HPC) are thought to promote a periportal ductular reaction (DR) and contribute to periportal fibrosis in HCV- and non-alcholic steatohepatitis (NASH)-associated liver diseases. IFN-gamma is a well recognized fibrotic inhibitor in vitro and in vivo. The present study investigate the role of IFN-gamma in HPC activation in chronic HBV infected patients and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treated mouse. Methods: Hepatic progenitor cells were quantified by Cytokeratin-19 (CK19) immunostaining in 110 HBV, as were oval cells (HPCs in rodents) in DDC treated wild-type and three kinds of IFN-gamma-associated gene knockout mice, including IFN-gamma-, IFN-gamma receptor- and interferon regulator factor (IRF)-1 knockout mice. Results: The CK19 staining score significantly correlates with inflammatory grade (r=0.61, P<0.001) and fibrotic stage (r=0.61, P<0.001) in 110 chronic HBV infected patients. 9-months IFN-gamma treatment resulted in decreased HPC numbers concomitant with reduced inflammatory and fibrotic degree in chronic HBV infection (13/18 patients). In line with HBV patients, the number of oval cells and DRs significantly increased in IFN-gamma knockout mice compare with wild-type mice after 4 weeks DDC treatment. Furthermore, elevated oval cells and DR also demonstrated in interferon regulator factor (IRF)-1, downstream of IFN-gamma signalling, knockout mice with 4 weeks DDC administration. Either IFN-gamma- or IRF-1 knockout mice showed serious fibrotic degree compare with wild-type mice in DDC model. Conclusions: Besides a role in anti-fibrosis, IFN-gamma inhibits HPC activation in chronic liver damage.