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Abstract
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.
Original language | English |
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Pages (from-to) | 485-96 |
Number of pages | 12 |
Journal | Annals of the New York Academy of Sciences |
Volume | 1110 |
DOIs | |
Publication status | Published - 1 Sept 2007 |
Keywords
- leukocyte adhesion
- endothelium
- semicarbazide-sensitive amine oxidases
- liver
- VAP-1
- SSAO
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- 1 Finished
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Lymphocyte Ligands for the Endothelial Adhesion Molecule Vascular Adhesion Protein-1
Adams, D. & Wakelam, M.
15/01/04 → 31/03/07
Project: Research Councils