Stromelysin-1 and macrophage metalloelastase expression in the intestinal mucosa of Crohn's disease patients treated with infliximab.
OBJECTIVE
The mechanism by which anti-tumor necrosis factor (TNF)-alpha therapy promotes rapid closure of fistulas and mucosal wound healing in Crohn's disease (CD) remains unclear. An ex-vivo model of gut T-cell mediated injury indicated that TNF-alpha blockade prevents tissue damage concomitant with matrix metalloproteinase (MMP) inhibition. We, therefore, hypothesized that the chimeric anti-TNF-alpha antibody infliximab facilitates wound healing in CD by downregulating tissue degrading MMPs. We focused on MMP-3 (stromelysin-1) and MMP-12 (macrophage metalloelastase) as these two enzymes have been linked to connective tissue destruction in CD.


METHODS
Endoscopic biopsies were taken from 10 CD patients immediately before and after 10 weeks of treatment with infliximab. Before treatment, biopsies were taken from macroscopically inflamed areas, and after treatment were collected from the same locations as before treatment. The degree of mucosal damage was assessed by using a histological scoring system. MMP transcripts were detected by in-situ hybridization on paraffin sections. MMP proteins were determined by immunoblotting on mucosal homogenates.


RESULTS
Six out of 10 patients had a clinical response to infliximab. MMP-3 and MMP-12 transcripts and proteins, which were highly expressed in CD inflamed mucosa, decreased after treatment in those patients who responded to infliximab. MMP-3 and MMP-12 downregulation was accompanied by a concomitant improvement of the histologic score. No change in MMP expression was found in nonresponders.


CONCLUSIONS
The downregulation of tissue degrading MMPs in CD mucosa may explain the wound repair capacity of infliximab in healing fistulas and ulcers.
Centre for Infectious Disease, Institute of Cellular and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK.
Antonio
A
Di Sabatino
Ulpu
U
Saarialho-Kere
Mark G
MG
Buckley
John N
JN
Gordon
Paolo
P
Biancheri
Laura
L
Rovedatti
Gino R
GR
Corazza
Thomas T
TT
Macdonald
Sylvia L F
SL
Pender
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003424:Crohn Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D053508:Matrix Metalloproteinase 12