title: Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment.
abstract: OBJECTIVE
  Inflammatory bowel disease (IBD) is characterized by a continuous influx of leukocytes into the gut wall. This migration is regulated by cell adhesion molecules (CAMs), and selective antimigration therapies have been developed. This study investigated the effect of infliximab therapy on the mucosal gene expression of CAMs in IBD.
  
  
  METHODS
  Mucosal gene expression of 69 leukocyte/endothelial CAMs and E-cadherin was investigated in 61 IBD patients before and after first infliximab infusion and in 12 normal controls, using Affymetrix gene expression microarrays. Quantitative reverse transcriptase-PCR (qRT-PCR), immunohistochemistry, and western blotting were used to confirm the microarray data.
  
  
  RESULTS
  When compared with control colons, the colonic mucosal gene expression of most leukocyte/endothelial adhesion molecules was upregulated and E-cadherin gene expression was downregulated in active colonic IBD (IBDc) before therapy, with no significant colonic gene expression differences between ulcerative colitis and colonic Crohn's disease. Infliximab therapy restored the upregulations of leukocyte CAMs in IBDc responders to infliximab that paralleled the disappearance of the inflammatory cells from the colonic lamina propria. Also, the colonic gene expression of endothelial CAMs and of most chemokines/chemokine receptors returned to normal after therapy in IBDc responders, and only CCL20 and CXCL1-2 expression remained increased after therapy in IBDc responders vs. control colons. When compared with control ileums, the ileal gene expression of MADCAM1, THY1, PECAM1, CCL28, CXCL1, -2, -5, -6, and -11, and IL8 was increased and CD58 expression was decreased in active ileal Crohn's disease (CDi) before therapy, and none of the genes remained dysregulated after therapy in CDi responders vs. control ileums. This microarray study identified a number of interesting targets for antiadhesion therapy including PECAM1, IL8, and CCL20, besides the currently studied α4β7 integrin-MADCAM1 axis.
  
  
  CONCLUSIONS
  Our data demonstrate that many leukocyte/endothelial CAMs and chemokines/chemokine receptors are upregulated in inflamed IBD mucosa. Controlling the inflammation with infliximab restores most of these dysregulations in IBD. These results show that at least part of the mechanism of anti-tumor necrosis factor-α therapy goes through downregulation of certain adhesion molecules.
authors.affiliation: Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Arijs
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.forename: Kathleen
authors.initials: K
authors.lastname: Machiels
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Steen
authors.forename: Katleen
authors.initials: K
authors.lastname: Lemaire
authors.forename: Anica
authors.initials: A
authors.lastname: Schraenen
authors.forename: Leentje
authors.initials: L
authors.lastname: Van Lommel
authors.forename: Roel
authors.initials: R
authors.lastname: Quintens
authors.forename: Gert
authors.initials: G
authors.lastname: Van Assche
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism*; D003092:Colitis / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003424:Crohn Disease / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007079:Ileitis / Q000378:metabolism; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism*; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D019707:Receptors, Chemokine / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D018925:Chemokines; D019707:Receptors, Chemokine; D000069285:Infliximab