Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome, and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner
Research output: Contribution to journal › Article
- University Hospital Jena, Germany
- BIOTIE THERAPIES CORPORATION
- Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
- MediCity Research Laboratory, University of Turku, Turku, Finland.
Objective: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD), wherein aberrant trafficking of mucosal T-cells from the gut is proposed to drive liver injury. Integral to this process is the ectoenzyme vascular adhesion protein (VAP)-1, which through its amine oxidase activity up-regulates mucosal addressin cell adhesion molecule (MAdCAM)-1 expression on hepatic endothelial vasculature, promoting recruitment of gut-tropic (7+) lymphocytes to the liver. Design: We examined VAP-1 expression in PSC patients, correlated levels with clinical characteristics, and determined the functional consequences of enzyme activation through varying substrate provision. Results: The intrahepatic enzyme activity of VAP-1 was elevated in PSC vs. immune-mediated disease controls and non-diseased liver (p<0.001), and adhesion of gut-tropic 7+ lymphocytes to hepatic endothelial cells under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). The natural substrate with highest VAP-1 efficiency (enzymatic rate) and efficacy (ability to induce functional MAdCAM-1 expression) was cysteamine – an amine known to be secreted by gut bacteria and colonic epithelium, capable of inducing colitis in mice. Elevated sVAP-1 levels predicted significantly worse transplant-free survival in PSC patients, independently (hazard ratio [HR]: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis. Conclusion: VAP-1 expression is heightened in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and levels of the circulating form predict clinical outcome.
|Early online date||20 Apr 2017|
|Publication status||E-pub ahead of print - 20 Apr 2017|
- VAP-1, Primary sclerosing cholangitis, Lymphocytes