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Hepatology. 2014 Feb;59(2):375-84. doi: 10.1002/hep.26571. Epub 2013 Dec 18.

Paracrine signals from liver sinusoidal endothelium regulate hepatitis C virus replication.

Author information

1
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.

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.

PMID:
23775568
PMCID:
PMC3992845
DOI:
10.1002/hep.26571
[Indexed for MEDLINE]
Free PMC Article

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