title: Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice.
abstract: Hepatitis B virus (HBV) infection is one of the most frequent causes of chronic liver disease worldwide. Because recent studies have suggested that Toll-like receptor (TLR)-based therapies may be a promising approach in the treatment of HBV infection, we studied the role of the local innate immune system of the liver as a possible mediator of this effect. Murine nonparenchymal cells, including Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs), were isolated from C57/BL6 wild-type or MyD88(-/-) mice and stimulated by agonists of TLR1 to TLR9. Supernatants were harvested and assayed for their antiviral activity against HBV in HBV-Met cells. No direct antiviral effect of TLR agonists could be observed. In controls (myeloid dendritic cells), TLR1, TLR3, TLR4, TLR7, and TLR9 activation lead to production of antiviral cytokines. By contrast, only supernatants from TLR3-stimulated and TLR4-stimulated KCs and TLR3-stimulated LSECs from wild-type mice were able to potently suppress HBV replication as assessed via Southern blotting. Similar results were found with cells from MyD88(-/-) mice, indicating that the effect was independent of this signaling pathway. Cellular HBV RNA and hepatitis B surface antigen or hepatitis B e antigen levels in supernatants remained unchanged. Using neutralizing antibodies, we demonstrated that the TLR3-mediated effect but not the TLR4-mediated effect is mediated exclusively through interferon-beta.
  
  
  CONCLUSIONS
  Our data indicate that the innate immune system of the liver can control HBV replication after activation by TLR agonists. This has implications for the development of TLR-based therapeutic approaches against HBV.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.forename: Zhongji
authors.initials: Z
authors.lastname: Meng
authors.forename: Martin
authors.initials: M
authors.lastname: Trippler
authors.forename: Ruth
authors.initials: R
authors.lastname: Broering
authors.forename: Agnes
authors.initials: A
authors.lastname: Szczeponek
authors.forename: Frank
authors.initials: F
authors.lastname: Krux
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.forename: Joerg F
authors.initials: JF
authors.lastname: Schlaak
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology; D007113:Immunity, Innate; D016899:Interferon-beta / Q000276:immunology; D007728:Kupffer Cells / Q000276:immunology; D008099:Liver / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051196:Toll-Like Receptor 3 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*
chemical_list: C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016899:Interferon-beta