Ligation of {{alpha}}4{beta}1 Integrin on Human Intestinal Mucosal Mesenchymal Cells Selectively Up-Regulates Membrane Type-1 Matrix Metalloproteinase and Confers a Migratory Phenotype

摘要

Human intestinal lamina propria mesenchymal cells show high surface expression of the 4ß1 integrin. Ligation of 4ß1 on mesenchymal cell lines with an activating monoclonal anti-4 antibody or vascular cell adhesion molecule-immunoglobulin (VCAM-IgG) leads to the appearance of activated forms of gelatinase A in culture supernatants, and the de novo expression of activated membrane type-1-matrix metalloproteinase (MT1-MMP). In functional assays, signaling through 4ß1 results in an increased capacity of mesenchymal cells to migrate through an artificial extracellular matrix, an effect inhibitable by excess tissue inhibitor of metalloproteinase-2. In organ cultures of human intestine, VCAM-IgG also up-regulates MT1-MMP, and in mucosal ulcers of inflammatory bowel disease patients, MT1-MMP transcripts are abundant, coincident with expression of VCAM-1 on cells at the ulcer margin. Collectively these results suggest that 4ß1-induced up-regulation of MT1-MMP may be a crucial factor in the migration of mesenchymal cells into ulcer beds during restitution of diseased gut mucosa.