Activation of vascular adhesion protein-1 on liver... : Hepatology (original) (raw)
Original Articles
Activation of vascular adhesion protein-1 on liver endothelium results in an NF-κB–dependent increase in lymphocyte adhesion
Lalor, Patricia F.1*; Sun, Phoebe Jun1; Weston, Chris J.1; Martin-Santos, Azucena1; Wakelam, Michael J. O.2; Adams, David H.1
1_Liver Research Group, Institute of Biomedical Research, University of Birmingham, Birmingham, UK_
2_Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK_
*Address reprint requests to: Liver Research Group, 5th Floor, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK
Email:[email protected]
Received 11 April 2006; Accepted 26 October 2006
Published online in Wiley InterScience (www.interscience.wiley.com).
Grant sponsor: European Commission; Grant Number: QLG1-CT-1999-00295; Grant sponsor: Medical Research Council; Grant Number: G0300101; Grant sponsor: National Institutes of Health; Grant Number: 5RO1AA014257.
Potential conflict of interest: Nothing to report.
fax: (44) 121-4158701
These authors contributed equally to this study.
Abstract
Vascular adhesion protein-1 (VAP-1) is an adhesion molecule and amine oxidase that is expressed at high levels in the human liver. It promotes leukocyte adhesion to the liver in vivo and drives lymphocyte transmigration across hepatic sinusoidal endothelial cells in vitro . We report that in addition to supporting leukocyte adhesion, provision of specific substrate to VAP-1 results in hepatic endothelial cell activation, which can be abrogated by treatment with the enzyme inhibitor semicarbazide. VAP-1–mediated activation was rapid; dependent upon nuclear factor-κB, phosphatidylinositol-3 kinase, and mitogen-activated protein kinase pathways; and led to upregulation of the adhesion molecules E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and secretion of the chemokine CXCL8. This response resulted in enhanced lymphocyte adhesion, was restricted to hepatic endothelial cells that expressed VAP-1, and was not observed in human umbilical vein endothelial cells.
Conclusion:
We propose that as well as directly promoting adhesion via interactions with the as yet unknown ligand, binding of enzyme substrate to VAP-1 can indirectly promote inflammatory cell recruitment via upregulation of adhesion molecules and chemokines. This response is likely to be important for the recruitment of leukocytes to the liver and suggests that VAP-1 inhibitors have therapeutic potential for treating chronic inflammatory liver disease.
Abbreviations: AOC3, amine oxidase, copper containing-3; EMSA, electrophoretic mobility shift assay; HSEC, hepatic sinusoidal endothelial cell; HUVEC, human umbilical vein endothelial cell; ICAM-1, intercellular adhesion molecule-1; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; NF-κB, nuclear factor-κB; PI3, phosphatidylinositol-3; SSAO, semicarbazide-sensitive amine oxidase; TNF-α, tumor necrosis factor-α; VAP-1, vascular adhesion protein-1.
Copyright © 2007 American Association for the Study of Liver Diseases.