title: Infliximab restores the dysfunctional matrix remodeling protein and growth factor gene expression in patients with inflammatory bowel disease.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), a disintegrin and metalloprotease with thrombospondin motifs [ADAM(TS)s] and growth factors are involved in inflammation and tissue damage and repair, all occurring in inflammatory bowel disease (IBD). We studied the impact of anti-inflammatory therapy with infliximab on mucosal expression of these tissue remodeling genes in patients with IBD.
  
  
  METHODS
  Mucosal gene expression of 23 MMPs, 4 TIMPs, 50 ADAM(TS)s, and 158 growth factors was investigated in 61 patients with IBD before and after the first infliximab therapy and in 12 controls, with microarrays and quantitative RT-PCR. Protein localization, mucosal gelatinase levels, and net gelatinolytic activity were investigated by immunohistochemistry, zymography analysis, and gelatin degradation assay, respectively.
  
  
  RESULTS
  In patients with active IBD before infliximab versus controls, gene expression of many MMPs, TIMPs, ADAM(TS)s, and growth factors was upregulated, whereas colonic expression of MMP28 and TGFA and ileal expression of ADAMDEC1 and AGT were downregulated. After controlling inflammation with infliximab, most gene dysregulations observed at baseline were restored in responders. Increased ratio of MMP1/TIMP1 expression at baseline in active IBD was restored in responders with colonic mucosal healing. With immunohistochemistry, protein localization differences of MMP1, MMP3, REG1A, and TIMP1 were shown between active IBD and control mucosa. With zymography analysis and gelatin degradation assay, higher gelatinase levels and net gelatinolytic activity were measured before infliximab and levels normalized after infliximab.
  
  
  CONCLUSIONS
  Our data suggest that suppression of inflammation results in the arrest of epithelial damage and subsequent mucosal healing. Therefore, the therapeutic potential of agents targeting MMPs or growth factors as primary therapy seems rather complex.
authors.affiliation: *Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine; †Laboratory of Immunobiology (Rega Institute for Medical Research), Department of Microbiology and Immunology; ‡Translational Cell and Tissue Research, Department of Imaging and Pathology; §Gene Expression Unit, Department of Cellular and Molecular Medicine; and ‖Leuven Food Science and Nutrition Research Centre (LFoRCe), KULeuven, Leuven, Belgium.
authors.forename: Magali
authors.initials: M
authors.lastname: de Bruyn
authors.forename: Kathleen
authors.initials: K
authors.lastname: Machiels
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vandooren
authors.forename: Bart
authors.initials: B
authors.lastname: Lemmens
authors.forename: Leentje
authors.initials: L
authors.lastname: Van Lommel
authors.forename: Christine
authors.initials: C
authors.lastname: Breynaert
authors.forename: Jan
authors.initials: J
authors.lastname: Van der Goten
authors.forename: Dominiek
authors.initials: D
authors.lastname: Staelens
authors.forename: Thomas
authors.initials: T
authors.lastname: Billiet
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrante
authors.forename: Gert
authors.initials: G
authors.lastname: Van Assche
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Ingrid
authors.initials: I
authors.lastname: Arijs
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000069285:Infliximab; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D011446:Prospective Studies; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D036341:Intercellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D000069285:Infliximab; D020782:Matrix Metalloproteinases