title: Transforming growth factor-β1 suppresses hepatitis B virus replication by the reduction of hepatocyte nuclear factor-4α expression.
abstract: Several studies have demonstrated that cytokine-mediated noncytopathic suppression of hepatitis B virus (HBV) replication may provide an alternative therapeutic strategy for the treatment of chronic hepatitis B infection. In our previous study, we showed that transforming growth factor-beta1 (TGF-β1) could effectively suppress HBV replication at physiological concentrations. Here, we provide more evidence that TGF-β1 specifically diminishes HBV core promoter activity, which subsequently results in a reduction in the level of viral pregenomic RNA (pgRNA), core protein (HBc), nucleocapsid, and consequently suppresses HBV replication. The hepatocyte nuclear factor 4alpha (HNF-4α) binding element(s) within the HBV core promoter region was characterized to be responsive for the inhibitory effect of TGF-β1 on HBV regulation. Furthermore, we found that TGF-β1 treatment significantly repressed HNF-4α expression at both mRNA and protein levels. We demonstrated that RNAi-mediated depletion of HNF-4α was sufficient to reduce HBc synthesis as TGF-β1 did. Prevention of HNF-4α degradation by treating with proteasome inhibitor MG132 also prevented the inhibitory effect of TGF-β1. Finally, we confirmed that HBV replication could be rescued by ectopic expression of HNF-4α in TGF-β1-treated cells. Our data clarify the mechanism by which TGF-β1 suppresses HBV replication, primarily through modulating the expression of HNF-4α gene.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Hsiang
authors.initials: MH
authors.lastname: Hong
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Chou
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Wu
authors.forename: Kuen-Nan
authors.initials: KN
authors.lastname: Tsai
authors.forename: Cheng-po
authors.initials: CP
authors.lastname: Hu
authors.forename: King-Song
authors.initials: KS
authors.lastname: Jeng
authors.forename: Mong-Liang
authors.initials: ML
authors.lastname: Chen
authors.forename: Chungming
authors.initials: C
authors.lastname: Chang
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D019251:Nucleocapsid / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D051557:Hepatocyte Nuclear Factor 4; D007976:Leupeptins; D012367:RNA, Viral; D053773:Transforming Growth Factor beta1; D014758:Viral Core Proteins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde