Leukocyte rolling is exclusively mediated by P‐selectinin colonic venules

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. 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‐α (TNF‐α) for 3 h. 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. DSS markedly increased production of TNF‐α in the colon. TNF‐α 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‐α. 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‐α. 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‐α. Moreover, P‐selectin‐dependent leukocyte rolling was found to be a precondition for TNF‐α‐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.British Journal of Pharmacology (2002) 135 , 1749–1756; doi: 10.1038/sj.bjp.0704638