title: Paracrine signals from liver sinusoidal endothelium regulate hepatitis C virus replication.
abstract: Hepatitis C virus (HCV) is a major cause of global morbidity, causing chronic liver injury that can progress to cirrhosis and hepatocellular carcinoma. The liver is a large and complex organ containing multiple cell types, including hepatocytes, sinusoidal endothelial cells (LSEC), Kupffer cells, and biliary epithelial cells. Hepatocytes are the major reservoir supporting HCV replication; however, the role of nonparenchymal cells in the viral lifecycle remains largely unexplored. LSEC secrete factors that promote HCV infection and transcript analysis identified bone morphogenetic protein 4 (BMP4) as a candidate endothelial-expressed proviral molecule. Recombinant BMP4 increased HCV replication and neutralization of BMP4 abrogated the proviral activity of LSEC-conditioned media. Importantly, BMP4 expression was negatively regulated by vascular endothelial growth factor A (VEGF-A) by way of a VEGF receptor-2 (VEGFR-2) primed activation of p38 MAPK. Consistent with our in vitro observations, we demonstrate that in normal liver VEGFR-2 is activated and BMP4 expression is suppressed. In contrast, in chronic liver disease including HCV infection where there is marked endothelial cell proliferation, we observed reduced endothelial cell VEGFR-2 activation and a concomitant increase in BMP4 expression.
  
  
  CONCLUSIONS
  These studies identify a role for LSEC and BMP4 in HCV infection and highlight BMP4 as a new therapeutic target for treating individuals with liver disease.
authors.affiliation: Hepatitis C Virus Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK; Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit, Institute for Biomedical Research, University of Birmingham, Birmingham, UK.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Rowe
authors.forename: Sukhdeep K
authors.initials: SK
authors.lastname: Galsinh
authors.forename: Garrick K
authors.initials: GK
authors.lastname: Wilson
authors.forename: Richard
authors.initials: R
authors.lastname: Parker
authors.forename: Sarah
authors.initials: S
authors.lastname: Durant
authors.forename: Catalin
authors.initials: C
authors.lastname: Lazar
authors.forename: Norica
authors.initials: N
authors.lastname: Branza-Nichita
authors.forename: Roy
authors.initials: R
authors.lastname: Bicknell
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Peter
authors.initials: P
authors.lastname: Balfe
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
mesh_terms: D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000473:pathology / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D048051:p38 Mitogen-Activated Protein Kinases