title: Leukocyte rolling is exclusively mediated by P-selectinin colonic venules.
abstract: 1. The objective of the present study was to examine the role of the endothelial selectins (i.e. P- and E-selectin) in leukocyte-endothelium interactions in colonic venules by use of intravital microscopy. 2. Balb/c mice were exposed to dextran sodium sulphate (DSS) in the drinking water for 5 days or treated intraperitoneally (i.p.) with tumour necrosis factor-alpha (TNF-alpha) for 3 h. 3. In DSS-treated mice, mRNA of both P- and E-selectin were expressed and leukocyte rolling and adhesion was increased to 27+/-3 cells min(-1) and 36+/-8 cells mm(-1), respectively. An anti-P-selectin antibody abolished DSS-induced leukocyte rolling, whereas an antibody against E-selectin had no effect. Established leukocyte adhesion was insensitive to inhibition of the selectins. 4. DSS markedly increased production of TNF-alpha in the colon. TNF-alpha increased leukocyte rolling to 22+/-3 cells min(-1) and adhesion to 45+/-4 cells mm(-1). Only inhibition of P-selectin significantly reduced (>94%) leukocyte rolling provoked by TNF-alpha. Leukocyte adhesion was not changed by late anti-P-selectin antibody treatment. In contrast, pretreatment with the anti-P-selectin antibody not only abolished leukocyte rolling but also completely inhibited firm adhesion in response to TNF-alpha. 5. This study demonstrates that P-selectin plays an important role in leukocyte rolling in colonic venules, both in experimental colitis and when stimulated with TNF-alpha. Moreover, P-selectin-dependent leukocyte rolling was found to be a precondition for TNF-alpha-induced firm adhesion. Thus, these findings suggest that P-selectin may be a key target to reduce pathological recruitment of inflammatory cells in the colon.
authors.affiliation: Department of Surgery, Malmö University Hospital, Lund University, 20502 Malmö, Sweden.
authors.forename: Ming Xiu
authors.initials: MX
authors.lastname: Wan
authors.forename: Amjid Ali
authors.initials: AA
authors.lastname: Riaz
authors.forename: Rene
authors.initials: R
authors.lastname: Schramm
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014699:Venules / Q000166:cytology / Q000502:physiology*
chemical_list: D019040:E-Selectin; D019007:P-Selectin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate