Abstract
BackgroundEnhanced expression of MAdCAM-1 (mucosal addressin cell adhesion molecule-1) is associated with the onset and progression of inflammatory bowel disease. The clinical significance of elevated MAdCAM-1 expression is supported by studies showing that immunoneutralization of MAdCAM-1, or its ligands reduce inflammation and mucosal damage in models of colitis. Interleukin-10 (IL-10) is an endogenous anti-inflammatory and immunomodulatory cytokine that has been shown to prevent inflammation and injury in several animal studies, however clinical IL-10 treatment remains insufficient because of difficulties in the route of IL-10 administration and its biological half-life. Here, we examined the ability of introducing an IL-10 expression vector into endothelial cultures to reduce responses to a proinflammatory cytokine, TNF-αMethodsA human IL-10 expression vector was transfected into high endothelial venular ('HEV') cells (SVEC4-10); we then examined TNF-α induced lymphocyte adhesion to lymphatic endothelial cells and TNF-α induced expression of MAdCAM-1 and compared these responses to control monolayers.ResultsTransfection of the IL-10 vector into endothelial cultures significantly reduced TNF-α induced, MAdCAM-1 dependent lymphocyte adhesion (compared to non-transfected cells). IL-10 transfected endothelial cells expressed less than half (46 ± 6.6%) of the MAdCAM-1 induced by TNF-α (set as 100%) in non-transfected (control) cells.ConclusionOur results suggest that gene therapy of the gut microvasculature with IL-10 vectors may be useful in the clinical treatment of IBD.
Highlights
Enhanced expression of MAdCAM-1 is associated with the onset and progression of inflammatory bowel disease
Infiltration of tissues by leukocytes is a common hallmark of many chronic inflammatory states that include the inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD)
The functional significance of increased appearance of MAdCAM-1 in IBD is supported by several reports which show that immunoneutralization of either MAdCAM-1 or its ligand, the α4β7 integrin, attenuate inflammation and mucosal damage in animal models of colitis [8,9,10]
Summary
Enhanced expression of MAdCAM-1 (mucosal addressin cell adhesion molecule-1) is associated with the onset and progression of inflammatory bowel disease. The clinical significance of elevated MAdCAM-1 expression is supported by studies showing that immunoneutralization of MAdCAM-1, or its ligands reduce inflammation and mucosal damage in models of colitis. In the setting of IBD, the expression of ECAMs like ICAM-1, VCAM-1, and MAdCAM1 (mucosal addressin cell adhesion molecule-1) is observed in experimental models of colitis, [2,3,4,5] and within the inflamed human colon in Crohn's disease and ulcerative colitis [6,7]. Since monoclonal antibodies directed against other ECAMs, VCAM-1, can as well reduce disease activity in colitis models [11,12,13,14], the literature suggests that MAdCAM-1 is probably necessary, but insufficient for the maximal penetrance of experimental and probably clinical IBD
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