Ligation of alpha4ss1 integrin on human intestinal mucosal mesenchymal cells selectively Up-regulates membrane type-1 matrix metalloproteinase and confers a migratory phenotype

S L Pender; M T Salmela; G Monteleone; D Schnapp; C McKenzie; J Spencer; S Fong; U Saarialho-Kere; T T MacDonald

doi:10.1016/s0002-9440(10)64834-1

Ligation of alpha4ss1 integrin on human intestinal mucosal mesenchymal cells selectively Up-regulates membrane type-1 matrix metalloproteinase and confers a migratory phenotype

Am J Pathol. 2000 Dec;157(6):1955-62. doi: 10.1016/s0002-9440(10)64834-1.

Authors

S L Pender¹, M T Salmela, G Monteleone, D Schnapp, C McKenzie, J Spencer, S Fong, U Saarialho-Kere, T T MacDonald

Affiliation

¹ Centre for Infection, Allergy, Inflammation and Repair, University of Southampton School of Medicine, Southampton, United Kingdom. s.pender@soton.ac.uk

Abstract

Human intestinal lamina propria mesenchymal cells show high surface expression of the alpha4ss1 integrin. Ligation of alpha4ss1 on mesenchymal cell lines with an activating monoclonal anti-alpha4 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 alpha4ss1 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 alpha4ss1-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies / pharmacology
Cell Movement / physiology
Embryo, Mammalian / metabolism
Embryo, Mammalian / physiology*
Enzyme Activation
Humans
Immunoglobulin G / pharmacology
Inflammatory Bowel Diseases / complications
Integrin alpha4beta1
Integrins / antagonists & inhibitors*
Integrins / immunology
Integrins / metabolism
Intestinal Mucosa / cytology
Intestinal Mucosa / embryology*
Intestinal Mucosa / metabolism
Matrix Metalloproteinase 1 / genetics
Matrix Metalloproteinase 1 / metabolism*
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 3 / genetics
Mesoderm / cytology
Mesoderm / metabolism*
Phenotype
RNA, Messenger / metabolism
Receptors, Lymphocyte Homing / antagonists & inhibitors*
Receptors, Lymphocyte Homing / immunology
Receptors, Lymphocyte Homing / metabolism
Tissue Distribution
Ulcer / etiology
Ulcer / metabolism
Up-Regulation
Vascular Cell Adhesion Molecule-1 / metabolism

Substances

Antibodies
Immunoglobulin G
Integrin alpha4beta1
Integrins
RNA, Messenger
Receptors, Lymphocyte Homing
Vascular Cell Adhesion Molecule-1
Matrix Metalloproteinase 3
Matrix Metalloproteinase 2
Matrix Metalloproteinase 1