title: Effect of cyclosporin A on cell adhesion molecules and leukocyte-endothelial cell interactions in experimental colitis.
abstract: BACKGROUND
  Cyclosporin A (CsA) is an immunosuppressive agent that is believed to act primarily through effects on T-helper lymphocyte function and proliferation. The aim of this study was to investigate whether modulation of leukocyte recruitment and expression of cell adhesion molecules contribute to the therapeutic efficacy of CsA in a model of experimental colitis.
  
  
  METHODS
  The therapeutic effects of CsA were assessed in mice with dextran sulfate sodium-induced colitis. Leukocyte-endothelial cell interactions were determined in colonic venules by intravital microscopy. The expression of cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhesion molecule 1 (MAd-CAM-1) was measured by the radiolabeled antibody technique.
  
  
  RESULTS
  Treatment with CsA (4 mg/kg/day) significantly improved the clinical course of colitis, decreasing weight loss, diarrhea, rectal bleeding, disease activity index, colon weight, and colonic shortening. Microscopic damage score, myeloperoxidase activity, tumor necrosis factor alpha (TNF-alpha), and interleukin-6 in colonic tissue were significantly diminished by CsA. CsA also significantly reduced ICAM-1 and VCAM-1, but not MAdCAM-1, expression in colitic mice. TNF-alpha-induced ICAM-1 and VCAM-1 expression in primary cultures of human umbilical vein endothelial cells was reduced by co-incubation with CsA. The reduction in adhesion molecule expression was followed by a marked decrease in leukocyte adhesion in colonic venules of colitic mice.
  
  
  CONCLUSIONS
  CsA ameliorates experimental colitis in mice. Reduced adhesion molecule expression resulting from diminished pro-inflammatory cytokine production and from a direct effect of CsA in endothelial cells decreases leukocyte recruitment into the inflamed intestine, contributing to this protective effect.
authors.affiliation: Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Soriano-Izquierdo
authors.forename: Meritxell
authors.initials: M
authors.lastname: Gironella
authors.forename: Anna
authors.initials: A
authors.lastname: Massaguer
authors.forename: Antonio
authors.initials: A
authors.lastname: Salas
authors.forename: Félix
authors.initials: F
authors.lastname: Gil
authors.forename: Josep M
authors.initials: JM
authors.lastname: Piqué
authors.forename: Julián
authors.initials: J
authors.lastname: Panés
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000187:drug effects*; D002450:Cell Communication / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D007136:Immunoglobulins / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009088:Mucoproteins / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects
chemical_list: D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine