Paracrine signals from liver sinusoidal endothelium regulate hepatitis C virus replication

Authors

  • Ian A. Rowe,

    1. Hepatitis C Virus Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
    2. Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
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  • Sukhdeep K. Galsinh,

    1. Hepatitis C Virus Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
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  • Garrick K. Wilson,

    1. Hepatitis C Virus Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
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  • Richard Parker,

    1. Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
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  • Sarah Durant,

    1. Angiogenesis Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
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  • Catalin Lazar,

    1. Viral Glycoproteins Department, Institute of Biochemistry, Bucharest, Romania
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  • Norica Branza-Nichita,

    1. Viral Glycoproteins Department, Institute of Biochemistry, Bucharest, Romania
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  • Roy Bicknell,

    1. Angiogenesis Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
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  • David H. Adams,

    1. Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
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  • Peter Balfe,

    1. Hepatitis C Virus Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
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  • Jane A. McKeating

    Corresponding author
    1. Hepatitis C Virus Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
    2. Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit, Institute for Biomedical Research, University of Birmingham, Birmingham, UK
    • Address reprint requests to: Professor Jane McKeating, Hepatitis C Virus Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham UK B15 2TT. E-mail: j.a.mckeating@bham.ac.uk fax: +44 (0)1214143599.

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  • Potential conflict of interest: Nothing to report.

  • Funded by the MRC, the Wellcome Trust, the National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit at University Hospital Birmingham NHS Foundation Trust and the University of Birmingham, the Romanian Academy Project 3 of the Institute of Biochemistry, and the European Social Fund. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

  • See Editorial on Page 363

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. Conclusion: 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. (Hepatology 2014;59:375–384)

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