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The lymphotoxin- β receptor (LT βR) pathway is critical for maintenance of organized lymphoid structures and is involved in the development of colitis. To investigate the mechanisms by which LT βR activation contributes to the pathology of chronic inflammation we used a soluble LT βR-Ig fusion protein as a competitive inhibitor of LT βR activation in the mouse model of chronic colitis induced by oral administration of dextran sulphate sodium. Strong expression of LT β which constitutes part of the LT α1 β2 ligand complex was detected in colonic tissue of mice with chronic colitis. Treatment with LT βR-Ig significantly attenuated the development and histological manifestations of the chronic inflammation and reduced the production of inflammatory cytokines such as TNF, IL-1 β, and IL-6. Moreover, LT βR-Ig treatment significantly down-regulated mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression, leading to reduced leucocyte rolling and sticking in postcapillary and collecting venules and reduced extravasation into the intestinal mucosa as quantified by in vivo fluorescence microscopy. Thus, LT βR pathway inhibition ameliorates DSS-induced experimental chronic colitis in mice by MAdCAM-1 down-regulation entailing reduced lymphocyte margination and extravasation into the inflamed mucosa. Therefore, a combined treatment with reagents blocking T cell-mediated perpetuation of chronic inflammation such as LT βR-Ig together with direct anti-inflammatory reagents such as TNF inhibitors could constitute a promising treatment strategy for chronic colitis. [ABSTRACT FROM AUTHOR]