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  • 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

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Hepatology
Original article
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
  1. Palak J Trivedi1,2,
  2. Joseph Tickle1,
  3. Mette Nåmdal Vesterhus3,4,
  4. Peter J Eddowes1,
  5. Tony Bruns5,6,
  6. Jani Vainio7,
  7. Richard Parker1,2,
  8. David Smith7,
  9. Evaggelia Liaskou1,
  10. Liv Wenche Thorbjørnsen3,4,
  11. Gideon M Hirschfield1,2,
  12. Kaisa Auvinen8,9,
  13. Stefan G Hubscher10,
  14. Marko Salmi8,9,
  15. David H Adams1,2,
  16. Chris J Weston1
    1. 1National Institute of Health Research Birmingham Liver Biomedical Research Centre Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
    2. 2Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK
    3. 3Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway
    4. 4National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
    5. 5Department of Internal Medicine IV, University Hospital Jena, Germany
    6. 6Center for Sepsis Control and Care, University Hospital Jena, Germany
    7. 7Biotie Therapies Corp., Turku, Finland
    8. 8MediCity Research Laboratory, University of Turku, Turku, Finland
    9. 9Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland
    10. 10Department of Cellular Pathology, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK
    1. Correspondence to Dr Chris J Weston, National Institute of Health Research (NIHR) Birmingham Liver Biomedical Research Centre Institute of Immunology and Immunotherapy, University of Birmingham, Wolfson Drive, Birmingham B152TT, UK; c.j.weston{at}bham.ac.uk

    Abstract

    Objective Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of IBD. This clinical association is linked pathologically to the recruitment of mucosal T cells to the liver, via vascular adhesion protein (VAP)-1-dependent enzyme activity. Our aim was to examine the expression, function and enzymatic activation of the ectoenzyme VAP-1 in patients with PSC.

    Design We examined VAP-1 expression in patients with PSC, correlated levels with clinical characteristics and determined the functional consequences of enzyme activation by specific enzyme substrates on hepatic endothelium.

    Results The intrahepatic enzyme activity of VAP-1 was elevated in PSC versus immune-mediated disease controls and non-diseased liver (p<0.001). The adhesion of gut-tropic α4β7+lymphocytes to hepatic endothelial cells in vitro under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). Of a number of natural VAP-1 substrates tested, cysteamine—which can be secreted by inflamed colonic epithelium and gut bacteria—was the most efficient (yielded the highest enzymatic rate) and efficacious in its ability to induce expression of functional mucosal addressin cell adhesion molecule-1 on hepatic endothelium. In a prospectively evaluated patient cohort with PSC, elevated serum soluble (s)VAP-1 levels predicted poorer transplant-free survival for patients, independently (HR: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis.

    Conclusions VAP-1 expression is increased in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and elevated levels of its circulating form predict clinical outcome in patients.

    • IMMUNE-MEDIATED LIVER DAMAGE
    • PRIMARY SCLEROSING CHOLANGITIS
    • INFLAMMATORY BOWEL DISEASE
    • ULCERATIVE COLITIS
    • MUCOSAL IMMUNITY

    This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

    https://doi.org/10.1136/gutjnl-2016-312354

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      Footnotes

      • Collaborators Professor Sirpa Jalkanen; MediCity Research Laboratory, University of Turku, Finland.

      • Contributors PJT conducted the experiments, performed statistical analysis and wrote all manuscript drafts to submission. JT performed immunohistochemical staining and approved the manuscript to submission. MNV, PE and LWT contributed serum samples from patients and approved the manuscript to submission. TB and EL provided critical insight into experimental design, assisted with cell culture and approved the manuscript to submission. JV and DS performed the VAP-1 immunofluorescence assays and approved the manuscript to submission. SGH reviewed immunohistochemical sections and approved the manuscript to submission. GH contributed patient samples, provided critical insight into study design and approved the manuscript to submission. DHA supervised the study and approved the manuscript to submission. CJW conceived and supervised the study, providing guidance into experimental design, approved the manuscript to submission and is the guarantor of the article.

      • Funding Wellcome Trust, 10.13039/100004440, 099907/Z/12/Z, National Institute for Health Research, 10.13039/501100000272.

      • Competing interests PJT is the recipient of a Wellcome Trust Clinical Research Fellowship (Grant ID: 099907/Z/12/Z). PJT, JT, PE, RP, EL, GMH, DHA and CJW received institutional salary support from the NIHR Birmingham Liver Biomedical Research Centre. This paper presents independent research supported by the Birmingham NIHR Liver Biomedical Research Centre based at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

      • Ethics approval Local Research and Ethics Committee Birmingham .

      • Provenance and peer review Not commissioned; externally peer reviewed.