title: Large hepatitis delta antigen activates STAT-3 and NF-κB via oxidative stress.
abstract: Hepatitis delta virus (HDV) coinfection or superinfection in hepatitis B virus (HBV)-infected patients results in a more aggressive liver disease, with more often fulminant forms and more rapid progression to cirrhosis and hepatocellular carcinoma. The mechanism(s) for this pejorative evolution remains unclear. To explore a specific HDV pathogenesis, we used a model of transient transfection of plasmids expressing the small (sHDAg or p24) or the large (LHDAg or p27) delta antigen in hepatocyte cell lines. We found that the production of reactive oxygen species was significantly higher in cells expressing p27. Consequently, p27 activated the signal transducer and activator of transcription-3 (STAT-3) and the nuclear factor kappa B (NF-κB) via the oxidative stress pathway. Moreover in the presence of antioxidants (PDTC, NAC) or calcium inhibitors (TMB-8, BAPTA-AM, Ruthenium Red), p27-induced activation of STAT-3 and NF-κB was dramatically reduced. Similarly, using a mutated form of p27, where the cysteine 211-isoprenylation residue was replaced by a serine, a significant reduction of STAT-3 and NF-κB activation was seen, suggesting the involvement of isoprenylation in this process. Additionally, we show that p27 is able to induce oxidative stress through activation of NADPH oxidase-4. These results provide insight into the mechanisms by which p27 can alter intracellular events relevant to HDV-related liver pathogenesis.
authors.affiliation: Service de bactériologie, virologie - hygiène, hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Laboratoire associé au Centre National de Référence des Hépatites B, C et Delta, Université Paris Nord, Paris.
authors.forename: V
authors.initials: V
authors.lastname: Williams
authors.forename: S
authors.initials: S
authors.lastname: Brichler
authors.forename: E
authors.initials: E
authors.lastname: Khan
authors.forename: M
authors.initials: M
authors.lastname: Chami
authors.forename: P
authors.initials: P
authors.lastname: Dény
authors.forename: D
authors.initials: D
authors.lastname: Kremsdorf
authors.forename: E
authors.initials: E
authors.lastname: Gordien
mesh_terms: D002460:Cell Line; D003698:Hepatitis Delta Virus / Q000276:immunology* / Q000472:pathogenicity*; D035923:Hepatitis delta Antigens / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis*; D018384:Oxidative Stress; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*
chemical_list: D035923:Hepatitis delta Antigens; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C442244:hepatitis delta virus large antigen