Suppression of Furin by Interferon-γ and the Impact on Hepatitis B Virus Antigen Biosynthesis in Human Hepatocytes

The roles of furin and intrahepatic cytokines in chronic heptatitis B virus (HBV) infection remain largely unknown. Here, we examined the relations between furin, IL-10, IL-12 beta, interferon (IFN)-gamma, programed death (PD)-1, programed death ligand (PD-L)1, and the suppression of hepatitis B e antigen (HBeAg) and surface antigen (HBsAg) biosynthesis. Liver biopsies were performed on 20 chronically HBV-infected (15 HBeAg-positive and 5 HBeAg-negative) patients to assess liver inflammation/fibrosis, and in:RNA levels of furin, IL-10, IL-12 beta, IFN-gamma, PD-1, and PD-L1 were assessed by quantitative real-time PCR. IFN-gamma mRNA abundance was associated with lower :furin mRNA levels and higher PD-1 and PD-L1 mRNA levels in liver tissue from HBeAg-positive patients. IL-10 and IL-12 beta mRNA levels positively correlated with IFN-gamma expression levels (P < 0.05). PD-L1 and furin mRNA levels were further assessed in IFN-gamma-stimulated hepatoma cell lines with (HepG2.2.15 cells) and without (HepG2 and Huh7 cells) HBV replication. IFN-gamma enhanced PD-L1 expression in hepatoma cells. In HepG2.2.15 cells, IFN-gamma further suppressed furin and HBeAg expression. Furin inhibition and knockdown in HepG2.2.15 cells also down-regulated HBeAg and HBsAg biosynthesis. These data suggest that IFN-gamma modulates the inflammatory response to avoid excessive hepatocyte damage through the enhancement of PD-1/PD-L1 expression, whereas furin suppression may contribute to a reduction in HBeAg/HBsAg biosynthesis. (Am J Pathol 2012, 181:19-25 http://dx.doi.org/10.1016/j.ajpath.2012.03.036)