Ligation of alpha4ss1 integrin on human intestinal mucosal mesenchymal cells selectively Up-regulates membrane type-1 matrix metalloproteinase and confers a migratory phenotype.
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.
Pender
S L
SL
Centre for Infection, Allergy, Inflammation and Repair, University of Southampton School of Medicine, Southampton, United Kingdom. s.pender@soton.ac.uk
Salmela
M T
MT
Monteleone
G
G
Schnapp
D
D
McKenzie
C
C
Spencer
J
J
Fong
S
S
Saarialho-Kere
U
U
MacDonald
T T
TT
D000906:Antibodies / Q000494:pharmacology; D002465:Cell Movement / Q000502:physiology; D004622:Embryo, Mammalian / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000150:complications; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution; D014456:Ulcer / Q000209:etiology / Q000378:metabolism; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000906:Antibodies; D007074:Immunoglobulin G; D039041:Integrin alpha4beta1; D016023:Integrins; D012333:RNA, Messenger; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1