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-12β, interferon (IFN)-γ, 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 mRNA levels of furin, IL-10, IL-12β, IFN-γ, PD-1, and PD-L1 were assessed by quantitative real-time PCR. IFN-γ 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-12β mRNA levels positively correlated with IFN-γ expression levels (P < 0.05). PD-L1 and furin mRNA levels were further assessed in IFN-γ-stimulated hepatoma cell lines with (HepG2.2.15 cells) and without (HepG2 and Huh7 cells) HBV replication. IFN-γ enhanced PD-L1 expression in hepatoma cells. In HepG2.2.15 cells, IFN-γ 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-γ 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.
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
Jia-Feng
JF
Wu
Hong-Yuan
HY
Hsu
Yen-Hsuan
YH
Ni
Huey-Ling
HL
Chen
Tzee-Chung
TC
Wu
Mei-Hwei
MH
Chang
D000293:Adolescent; D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000821:virology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D045683:Furin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D055785:Gene Knockdown Techniques; D006511:Hepatitis B Antigens / Q000096:biosynthesis*; D006514:Hepatitis B Surface Antigens / Q000096:biosynthesis; D006513:Hepatitis B e Antigens / Q000096:biosynthesis; D019694:Hepatitis B, Chronic / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000276:immunology; D008113:Liver Neoplasms / Q000276:immunology / Q000821:virology; D008297:Male; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000276:immunology; D055815:Young Adult
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; D006511:Hepatitis B Antigens; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D007371:Interferon-gamma; D045683:Furin