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

Abstract

CD151, a member of the tetraspanin family of receptors, is a lateral organizer and modulator of activity of several families of transmembrane proteins. It has been implicated in the development and progression of several cancers, but its role in chronic inflammatory disease is less well understood. Here we show that CD151 is upregulated by distinct microenvironmental signals in a range of chronic inflammatory liver diseases and in primary liver cancer, in which it supports lymphocyte recruitment. CD151 was highly expressed in endothelial cells of the hepatic sinusoids and neovessels developing in fibrotic septa and tumor margins. Primary cultures of human hepatic sinusoidal endothelial cells (HSECs) expressed CD151 at the cell membrane and in intracellular vesicles. CD151 was upregulated by VEGF and HepG2 conditioned media but not by proinflammatory cytokines. Confocal microscopy confirmed that CD151 colocalized with the endothelial adhesion molecule/immunoglobulin superfamily member, VCAM-1. Functional flow-based adhesion assays with primary human lymphocytes and HSECs demonstrated a 40% reduction of lymphocyte adhesion with CD151 blockade. Inhibition of lymphocyte adhesion was similar between VCAM-1 blockade and a combination of CD151/VCAM-1 blockade, suggesting a collaborative role between the two receptors. These studies demonstrate that CD151 is upregulated within the liver during chronic inflammation, where it supports lymphocyte recruitment via liver endothelium. We propose that CD151 regulates the activity of VCAM-1 during lymphocyte recruitment to the human liver and could be a novel anti-inflammatory target in chronic liver disease and hepatocellular cancer prevention.NEW & NOTEWORTHY 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 carcinoma (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.

Publication DOI: https://doi.org/10.1152/ajpgi.00411.2016
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
Additional Information: Licensed under Creative Commons Attribution CC-BY 4.0: © the American Physiological Society.
Uncontrolled Keywords: Carcinoma, Hepatocellular/metabolism,Cell Adhesion/physiology,End Stage Liver Disease/metabolism,Humans,Liver/drug effects,Liver Neoplasms/metabolism,Lymphocytes/drug effects,Tetraspanin 24/metabolism,Up-Regulation/drug effects,Vascular Cell Adhesion Molecule-1/metabolism,Vascular Endothelial Growth Factor A/pharmacology
Publication ISSN: 1522-1547
Last Modified: 03 Apr 2024 07:34
Date Deposited: 11 Nov 2022 08:30
Full Text Link:
Related URLs: https://journal ... jpgi.00411.2016 (Publisher URL)
PURE Output Type: Article
Published Date: 2017-08-01
Accepted Date: 2017-05-03
Authors: Wadkin, James C R
Patten, Daniel A
Kamarajah, Sivesh K
Shepherd, Emma L (ORCID Profile 0000-0002-1345-1746)
Novitskaya, Vera
Berditchevski, Fedor
Adams, David H
Weston, Chris J
Shetty, Shishir

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