Back to Search
Start Over
Paracrine signals from liver sinusoidal endothelium regulate hepatitis C virus replication
- Source :
- Hepatology. 59:375-384
- Publication Year :
- 2013
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2013.
-
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)
- Subjects :
- Hepatology
Hepatitis C virus
Biology
medicine.disease_cause
medicine.disease
Chronic liver disease
3. Good health
Vascular endothelial growth factor B
Endothelial stem cell
Liver disease
Vascular endothelial growth factor A
Viral replication
Vascular endothelial growth factor C
embryonic structures
Immunology
medicine
Subjects
Details
- ISSN :
- 02709139
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Hepatology
- Accession number :
- edsair.doi...........8da8cb21b43f46289ca194af9c9c0594