Imbalance of stromelysin-1 and TIMP-1 in the mucosal lesions of children with inflammatory bowel disease.
BACKGROUND
Degradation of the extracellular matrix and ulceration of the mucosa are major features of inflammatory bowel disease (IBD). One of the most important enzymes in degrading the matrix and produced in excess by cytokine activated stromal cells, is stromelysin-1. The activity of stromelysin-1 is controlled by tissue inhibitor of metalloproteinase (TIMP-1), its natural inhibitor. In model systems excess stromelysin-1 produces mucosal degradation.


METHODS
Quantitative competitive RT-PCR was used to analyse stromelysin-1 and TIMP-1 transcripts; western blotting was used to measure the amount of stromelysin-1 and TIMP-1 protein in biopsy samples from children with IBD.


RESULTS
In biopsies from patients with active Crohn's disease (n=24), ulcerative colitis (n=23), and controls (n=16), TIMP-1 transcripts and protein were abundant and unchanged. Stromelysin-1 transcripts and protein were markedly elevated in mucosal biopsies obtained from inflamed sites of patients with active IBD but were not elevated in adjacent endoscopically normal mucosa (n=10). Elevated levels of stromelysin-1 transcripts in active Crohn's disease (n=5) returned to normal levels following treatment with enteral nutrition.


CONCLUSIONS
Stromelysin-1 is markedly overexpressed at inflamed sites in patients with IBD whereas TIMP-1 remains unaltered. Excess stromelysin-1 is likely to be responsible for loss of mucosal integrity in IBD.
Heuschkel
R B
RB
Department of Pediatric Gastroenterology, Royal Free and University College Medical School, London, UK.
MacDonald
T T
TT
Monteleone
G
G
Bajaj-Elliott
M
M
Smith
J A
JA
Pender
S L
SL
D015153:Blotting, Western; D002648:Child; D003093:Colitis, Ulcerative / Q000201:enzymology / Q000378:metabolism; D003424:Crohn Disease / Q000201:enzymology / Q000378:metabolism; D004750:Enteral Nutrition; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000201:enzymology* / Q000378:metabolism / Q000628:therapy; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019278:Matrix Metalloproteinase 3