Print Email Facebook Twitter Effect of the anti-tumor necrosis factor-α antibody infliximab on the ex vivo mucosal matrix metalloproteinase-proteolytic phenotype in inflammatory bowel disease Title Effect of the anti-tumor necrosis factor-α antibody infliximab on the ex vivo mucosal matrix metalloproteinase-proteolytic phenotype in inflammatory bowel disease Author Meijer, M.J. Mieremet-Ooms, M.A.C. van Duijn, W. van der Zon, A.M. Hanemaaijer, R. Verheijen, J.H. van Hogezand, R.A. Lamers, C.B.H.W. Verspaget, H.W. TNO Kwaliteit van Leven Publication year 2007 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-α 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-α protein, activity and/or mRNA levels. All patients were genotyped for functional TNF-α, 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. Copyright © 2006 Crohn's & Colitis Foundation of America, Inc. Subject Biomedical ResearchInflammatory bowel diseaseInfliximabMatrix metalloproteinaseTissue inhibitor of metalloproteinaseTumor necrosis factor-alphaazathioprinecyclosporingelatinase Agelatinase Binfliximabinterstitial collagenasemesalazinemessenger RNApokeweed mitogensteroidstromelysintissue inhibitor of metalloproteinase 1tissue inhibitor of metalloproteinase 2tumor necrosis factor alpha antibodyadolescentadultagedarticleclinical articlecontrolled studyCrohn diseasedrug effectenteritisexplantfemalegenotypehumanhuman tissueintestine mucosamalepriority journalprotein degradationprotein expressionsingle nucleotide polymorphismulcerative colitisAdolescentAdultAgedAntibodies, MonoclonalColitis, UlcerativeCrohn DiseaseDown-RegulationFemaleHumansIntestinal MucosaMaleMatrix MetalloproteinasesMiddle AgedPhenotypePolymorphism, Single NucleotideReverse Transcriptase Polymerase Chain ReactionTissue Culture TechniquesTissue Inhibitor of MetalloproteinasesTumor Necrosis Factor-alpha To reference this document use: http://resolver.tudelft.nl/uuid:f3f265c6-0bfc-4718-adc6-7baca58b9148 DOI https://doi.org/10.1002/ibd.20051 TNO identifier 239843 ISSN 1078-0998 Source Inflammatory Bowel Diseases, 13 (2), 200-210 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.