Vascular adhesion protein-1 as a potential therapeutic target in liver disease.
Vascular adhesion protein-1 (VAP-1) is a homodimeric, transmembrane sialoglycoprotein, and amine-oxidase enzyme constitutively expressed by hepatic endothelial cells, and as a soluble protein in serum (sVAP-1). VAP-1 mediates leukocyte adhesion and migration in an enzyme activity-dependent manner. We wished to determine whether VAP-1 blockade reduces leukocyte recruitment in inflammatory liver disease, and the mechanism by which this occurs. Our results show that VAP-1 is upregulated in the liver and serum of patients with inflammatory liver disease. Expression is maintained on hepatic sinusoidal endothelial cells (HSECs) isolated from explanted livers. Blockade of VAP-1 activity modestly decreases migration of normal lymphocytes across HSECs but has significant effects on the migration of peripheral blood lymphocytes (PBLs) and liver-derived lymphocytes across HSECs. Engagement of VAP-1 results in PI3-kinase-dependent NF-kappaB activation and increased chemokine and adhesion molecule expression. Thus complex mechanisms regulate VAP-1-mediated recruitment of leukocytes. Direct binding to endothelial VAP-1 protein, indirect enzyme-dependent activation of other endothelial adhesive pathways, and activation of leukocyte by VAP-1 ligand occupancy all contribute to adhesion. The restricted expression of VAP-1 and increased production of sVAP-1 in inflammatory liver disease confirm the validity of this molecule as a therapeutic target.
Lalor
Patricia F
PF
Liver Research Laboratory, Institute of Biomedical Research, Division of Medicine. University of Birmingham, Birmingham B15 2TT UK. p.f.lalor@bham.ac.uk
Tuncer
Ceren
C
Weston
Chris
C
Martin-Santos
Azucena
A
Smith
David J
DJ
Adams
David H
DH
D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement; D006801:Humans; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism* / Q000628:therapy*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism
D015815:Cell Adhesion Molecules; D016328:NF-kappa B