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ON001. Anti-TNF antibodies down-regulate mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) in inflammatory bowel disease

A. Di Sabatino1, L. Rovedatti1, S. Vetrano2, P. Biancheri1, F. Vidali1, M. Guerci1, S. Danese2, G.R. Corazza1

1First Department of Medicine, Fondazione IRCCS Policlinico S. Matteo, University of Pavia, Pavia, Italy; 2Division of Gastroenterology, IRCCS Istituto Clinico Humanitas, Milan, Italy

Background and Aims: Mucosal addressin cell-adhesion molecule-1 (MAdCAM-1), selectively expressed on gut endothelial cells, and integrin α4β7, expressed on lymphocytes, is critical in lymphocyte homing to the gut mucosa. During exacerbations of inflammatory bowel disease (IBD), the expression of MAdCAM-1 is up-regulated and promotes the sustained recruitment of circulating α4β7+ T cells to the gut with the establishment of chronic bowel inflammation. Pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin-1, are known to up-regulate MAdCAM-1 expression on endothelium in inflamed tissue. On this basis, we explored in ex vivo experiments the influence of TNF-α-blockade on mucosal MAdCAM-1 expression in IBD.

Materials and Methods: Multiple ileal and/or colonic biopsies were collected from inflamed mucosa of 15 active IBD patients (8 with Crohn's disease and 7 with ulcerative colitis) and from normal mucosa of 10 control subjects. Some of the biopsies were snap-frozen in liquid nitrogen, others were placed on iron grids in the central well of an organ culture dish in a tight container with 95% O2/5% CO2 at 37°C, and cultured for 24h with 10 μg/ml infliximab or 10 μg/ml adalimumab or their isotype control (human IgG1), in the presence or absence of the p38 mitogen-activated protein kinase inhibitor SB203580. MAdCAM-1 expression was determined on tissue homogenates by Western Blotting and normalized for β-actin.

Results: As expected, MAdCAM-1 expression was significantly (p < 0.001) higher in inflamed IBD mucosa than in normal mucosa. No appreciable difference between Crohn's disease and ulcerative colitis samples was observed in the expression of MAdCAM-1. A dramatic down-regulation of MAdCAM-1 was observed in IBD biopsies cultured with infliximab or adalimumab in comparison to IgG1-treated biopsies. No significant difference was found between infliximab and adalimumab in reducing MAdCAM-1 expression. The p38 mitogen-activated protein kinase inhibitor SB203580 neutralised the down-regulatory effect of both infliximab and adalimumab on MAdCAM-1.

Conclusions: Our findings show an ex vivo inhibitory effect of both infliximab and adalimumab on MAdCAM-1 expression in IBD. MAPK signalling is required to transduce the anti-TNF-induced down-regulation of MAdCAM-1. This suggests a novel mechanism of action of anti-TNF antibodies in IBD, i.e. the amelioration of mucosal inflammation through the inhibition of T cell recruitment to the gut.