PECAM-1 (CD 31) mediates transendothelial leukocyte migration in experimental colitis.
Transendothelial migration of circulating leukocytes into the colonic wall is a key step in the development of the inflammatory infiltrate in inflammatory bowel disease (IBD). The platelet-endothelial cell adhesion molecule-1 PECAM-1 (CD31) is expressed in the tight junction area of endothelial cells, where it is supposed to support the transmigration process. The aim of this study was to determine the role of PECAM-1 in experimental IBD and to show whether blockade of PECAM-1 has therapeutic effects. Chronic colitis was induced in female BALB/c mice by cyclic oral administration of dextran sodium sulfate (DSS) 3% (wt/vol). Expression of PECAM-1 was visualized by immunohistochemistry. In the treatment group animals received 1 mg/kg anti-PECAM-1 (2H8) ip daily starting on day 26. On day 30 leukocyte adhesion and migration was measured during N(2)O-isoflurane anesthesia in the distal colon by intravital microscopy. Disease activity index (DAI), histology, and MPO levels were compared with healthy and diseased controls. PECAM-1 was expressed in colitic mice. Chronic DSS colitis was characterized by a marked increase in rolling, adherent, and transmigrated leukocytes compared with healthy controls. Immunoblockade of PECAM-1 reduced leukocyte transmigration significantly and also diminished leukocyte rolling and sticking in an indirect manner. It also resulted in a significantly diminished DAI and MPO levels, as well as an amelioration of the histological inflammation score. PECAM-1 plays an important role in transendothelial leukocyte migration in DSS colitis. PECAM-1 could be a novel target for antibody-based treatment in IBD.
Rijcken
Emile
E
Dept. of General Surgery, Muenster University Hospital, Waldeyerstrasse 1, D-48149 Muenster, Germany. rijcken@uni-muenster.de
Mennigen
Rudolf B
RB
Schaefer
Sebastian D
SD
Laukoetter
Mike G
MG
Anthoni
Christoph
C
Spiegel
Hans-Ullrich
HU
Bruewer
Matthias
M
Senninger
Norbert
N
Krieglstein
Christian F
CF
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology / Q000627:therapeutic use; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018715:Microscopy, Video; D009195:Peroxidase / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016264:Dextran Sulfate; D009195:Peroxidase