The
lymphotoxin-beta receptor (LTbetaR) pathway is critical for maintenance of organized lymphoid structures and is involved in the development of
colitis. To investigate the mechanisms by which LTbetaR activation contributes to the pathology of chronic
inflammation we used a soluble LTbetaR-Ig fusion
protein as a competitive inhibitor of LTbetaR activation in the mouse model of chronic
colitis induced by
oral administration of
dextran sulphate
sodium. Strong expression of LTbeta which constitutes part of the LTalpha(1)beta(2)
ligand complex was detected in colonic tissue of mice with chronic
colitis. Treatment with LTbetaR-Ig significantly attenuated the development and histological manifestations of the chronic
inflammation and reduced the production of inflammatory
cytokines such as TNF, IL-1beta, and
IL-6. Moreover, LTbetaR-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, LTbetaR 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 LTbetaR-Ig together with direct anti-inflammatory
reagents such as
TNF inhibitors could constitute a promising treatment strategy for chronic
colitis.