Activation of vascular adhesion protein-1 on liver endothelium results in an NF-kappaB-dependent increase in lymphocyte adhesion.
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-kappaB, 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.


CONCLUSIONS
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.
Lalor
Patricia F
PF
Liver Research Group, Institute of Biomedical Research, University of Birmingham, Birmingham, UK. p.f.lalor@bham.ac.uk
Sun
Phoebe Jun
PJ
Weston
Chris J
CJ
Martin-Santos
Azucena
A
Wakelam
Michael J O
MJ
Adams
David H
DH
D006631:Amine Oxidase (Copper-Containing) / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology* / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D016209:Interleukin-8; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing)