title: Effect of the anti-tumor necrosis factor-alpha antibody infliximab on the ex vivo mucosal matrix metalloproteinase-proteolytic phenotype in inflammatory bowel disease.
abstract: 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.
authors.affiliation: Leiden University Medical Center, Department of Gastroenterology-Hepatology, Leiden, The Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Meijer
authors.forename: Marij A C
authors.initials: MA
authors.lastname: Mieremet-Ooms
authors.forename: Wim
authors.initials: W
authors.lastname: van Duijn
authors.forename: Annie M
authors.initials: AM
authors.lastname: van der Zon
authors.forename: Roeland
authors.initials: R
authors.lastname: Hanemaaijer
authors.forename: Jan H
authors.initials: JH
authors.lastname: Verheijen
authors.forename: Ruud A
authors.initials: RA
authors.lastname: van Hogezand
authors.forename: Cornelis B H W
authors.initials: CB
authors.lastname: Lamers
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000201:enzymology* / Q000235:genetics; D003424:Crohn Disease / Q000201:enzymology* / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000201:enzymology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046509:Tissue Culture Techniques; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D020782:Matrix Metalloproteinases