Research Article: CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma

Date Published: August 1, 2017

Publisher: American Physiological Society

Author(s): James C. R. Wadkin, Daniel A. Patten, Sivesh K. Kamarajah, Emma L. Shepherd, Vera Novitskaya, Fedor Berditchevski, David H. Adams, Chris J. Weston, Shishir Shetty.


Chronic hepatitis is characterized by lymphocyte accumulation in liver tissue, which drives fibrosis and carcinogenesis. Here, we demonstrate for the first time that the tetraspanin CD151 supports lymphocyte adhesion to liver endothelium. We show that CD151 is upregulated in chronic liver disease and hepatocellular cancer (HCC) and is regulated on endothelium by tissue remodeling and procarcinogenic factors. These regulatory and functional studies identify CD151 as a potential therapeutic target to treat liver fibrosis and HCC.

Partial Text

Tetraspanins are a family of proteins that contribute to several aspects of cell-cell interactions. CD151 is involved in cell-to-cell communication, wound healing, platelet aggregation, cell trafficking, and angiogenesis (7, 15, 34, 38). In addition, it has been reported to play a role in leukocyte adhesion to human umbilical vein endothelial cells. To our knowledge, a role for CD151 in leukocyte recruitment to specialized vascular beds has not been investigated. A key step in leukocyte recruitment to the liver is binding to HSECs. These endothelial cells have a distinct phenotype compared with conventional venular endothelium determined by the functional requirements of their microenvironment (9, 14). We have previously shown that, following isolation from human liver tissue, these endothelial cells maintain their unique phenotype and junctional complexes as well as their functional characteristics (29). In the present study, we have characterized the expression of CD151 in normal and diseased human liver and found it to be upregulated at sites of leukocyte recruitment, including the hepatic sinusoids and neovessels of the fibrous septa as well as on vessels in HCC and surrounding peritumoral stroma. Isolated HSECs maintain expression of CD151, allowing us to study the regulation and function of CD151 in these cells. Detailed analysis of CD151 cellular distribution suggests that it is mobilized to the cell surface from intracellular vesicles, and, although we detected the protein at chronic inflammatory sites in vivo, expression of CD151 was not regulated in vitro by the proinflammatory cytokines TNF-α or IFN-γ in contrast to many of the standard endothelial adhesion receptors. Previous studies on epithelial cells have demonstrated that CD151 is upregulated by chronic exposure to TGF-β (hepatocyte cell line) (17) and suppressed by hypoxia (colon cancer cell line) (12). In our study, neither stimulation of HSECs with TGF-β nor exposure to hypoxia altered CD151 expression, suggesting that the regulation of CD151 differs between endothelial cells and epithelial cells. However, expression was increased by treatment with growth factors, specifically VEGF, and by culture in culture supernatant from an HCC cell line. These findings suggest that CD151 in endothelial cells is regulated by microenvironmental signals induced by tissue remodeling or those present in the tumor microenvironment.

S. Shetty was funded by a Wellcome Trust Intermediate Clinical Fellowship (097162/Z/11/Z). D. Patten and S. Shetty were also funded by the Queen Elizabeth Hospital Birmingham Charity. C. Weston and E. Shepherd were funded by a Wellcome Trust Programme grant (091019/Z/09/Z). J. Wadkin and S. Kamarajah were funded by bursaries from Cancer Research UK. This paper presents independent research supported by the NIHR Birmingham Liver Biomedical Research Unit based at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

No conflicts of interest, financial or otherwise, are declared by the authors.

D.A.P., F.B., C.J.W., and S.S. conceived and designed research; J.C.W., D.A.P., S.K., E.L.S., and V.N. performed experiments; J.C.W., D.A.P., S.K., E.L.S., and C.J.W. analyzed data; D.A.P. and C.J.W. interpreted results of experiments; J.C.W., D.A.P., D.H.A., C.J.W., and S.S. drafted manuscript; D.A.P. and S.S. prepared figures; D.A.P. edited and revised manuscript; F.B., D.H.A., and C.J.W. approved final version of manuscript.




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