The adhesion molecules known as selectins mediate the capture of neutrophils from the bloodstream. We have previously reported that ligation and cross-linking of L-selectin on the neutrophil surface enhances the adhesive function of  2 -integrins in a synergistic manner with chemotactic agonists. In this work, we examined degranulation and adhesion of neutrophils in response to cross-linking of L-selectin and addition of interleukin-8. Cross-linking of L-selectin induced priming of degranulation that was similar to that observed with the alkaloid cytochalasin B. Activation mediated by L-selectin of neutrophil shape change and adhesion through CD11b/CD18 were strongly blocked by Merck C, an imidazole-based inhibitor of p38 mitogen-activated protein kinase (MAPK), but not by a structurally similar non-binding regioisomer. Priming by L-selectin of the release of secondary, tertiary, and secretory, but not primary, granules was blocked by inhibition of p38 MAPK. Peak phosphorylation of p38 MAPK was observed within 1 min of cross-linking L-selectin, whereas phosphorylation of ERK1/2 was highest at 10 min. Phosphorylation of p38 MAPK, but not ERK1/2, was inhibited by Merck C. These data suggest that signal transduction as a result of clustering L-selectin utilizes p38 MAPK to effect neutrophil shape change, integrin activation, and the release of secondary, tertiary, and secretory granules.Neutrophils circulate in the vasculature in a passive state and become more adhesive upon stimulation at sites of inflammation. Margination to the vessel wall and subsequent transmigration and phagocytosis (1) requires a number of surface proteins, including the  2 -integrins and the selectins, as mediators of adherence to the endothelium (2-5). A sequence of molecular and biophysical events has been identified that facilitates neutrophil activation and increased adherence during the acute inflammatory response in vivo. Neutrophils entering post-capillary venules adjacent to inflammatory foci develop transient rolling adhesive interactions with endothelium via selectins (6). Following exposure to inflammatory cytokines such as tumor necrosis factor and interleukin-1, endothelial cells are induced to express E-selectin and P-selectin (6). Several surface glycoproteins on neutrophils, including L-selectin and P-selectin glycoprotein ligand 1, present oligosaccharide moieties that serve as counter receptors for E-selectin and P-selectin. In conjunction with neutrophil membrane L-selectin, which recognizes oligosaccharides on endothelial cells,
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