Effect of the anti-tumor necrosis factor-α antibody infliximab on the ex vivo mucosal matrix metalloproteinase–proteolytic phenotype in inflammatory bowel disease
✍ Scribed by Martin J. Meijer; Marij A.C. Mieremet-Ooms; Wim van Duijn; Annie M. van der Zon; Roeland Hanemaaijer; Jan H. Verheijen; Ruud A. van Hogezand; Cornelis B.H.W. Lamers; Hein W. Verspaget
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 478 KB
- Volume
- 13
- Category
- Article
- ISSN
- 1078-0998
No coin nor oath required. For personal study only.
✦ Synopsis
Background:
Previous studies have shown an upregulation of matrix metalloproteinases (mmps) in intestinal tissue of patients with inflammatory bowel disease (ibd) and significant clinical improvement after administration of the anti-tnf-a antibody infliximab. the aims of our study were to determine expression and secretion of mmp-1, -2, -3, -9, and their inhibitors timp-1, -2 by ibd versus control intestinal mucosa ex vivo and to assess the regulatory capacity by infliximab of the proteolytic phenotype.
Methods:
Intestinal mucosal explants from 20 ibd and 15 control patients were cultured with or without infliximab and/or the t-cell activator pokeweed mitogen (pwm). explants and culture supernatants were analyzed for mmps, timps, and tnf-alpha protein, activity and/or mrna levels. all patients were genotyped for functional tnf-alpha, mmp, and timp single nucleotide polymorphism (snp) loci.
Results:
Expression of mmp and timp protein/activity in basal medium was higher in ibd versus control explants. dependent on genotype at snp loci, infliximab downregulated mmp-1, -3, and -9 relative to timp-1 and -2 and also decreased mmp-1 and -3 activities, while pwm enhanced these levels, partly counteracted again by infliximab. the expression of mmp-2 relative to timp did not change by treatment with infliximab and/or pwm.
Conclusions:
The high expression of mmps in patients with ibd suggests a role for these proteinases in the pathogenesis of this disease. infliximab seems to induce a genotype-associated matrix protective phenotype, which may contribute to the observed therapeutic efficacy of this drug in ibd, particularly at the mucosal surface.