Liaskou, Evaggelia (2010)
Ph.D. thesis, University of Birmingham.
Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a tissue–specific protein that promotes α4β7+ lymphocyte recruitment on gut mucosal endothelium, playing an important role in the development of inflammatory bowel disease (IBD). Recent studies have reported its expression in liver diseases such as primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) that complicate IBD, therefore understanding the factors that drive hepatic expression of MAdCAM-1 might elucidate the pathogenesis of these diseases. In vitro stimulation of HSEC with tumor necrosis factor-α (TNFα) and methylamine, the physiological substrate of vascular adhesion protein-1 (VAP-1), as well as with the end products of methylamine deamination by VAP-1, resulted in increased levels of secreted and cell surface MAdCAM-1 protein that was able to support binding of α4β7+ lymphocytes under flow conditions. In vivo stimulation of mice that expressed hVAP-1 as a transgene, with methylamine, induced expression of MAdCAM-1 in Peyer’s patches and mesenteric lymph nodes, validating the effect of VAP-1 enzyme activity. In conclusion, we report for the first time that MAdCAM-1 is normally present in human liver and is further induced upon TNFα and methylamine stimulation resulting in the recruitment of mucosal cells to the liver, thus sustaining a destructive inflammatoty influx responsible for the establishment of chronic inflammation.
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