PEPTIDES INHIBIT SELECTIN-MEDIATED CELL-ADHESION IN-VITRO, AND NEUTROPHIL INFLUX INTO INFLAMMATORY SITES IN-VIVO

The selectins are cell adhesion molecules whose carbohydrate-binding d omain (C-type lectin) is thought to be involved in leukocyte adhesion to activated vascular endothelium in the inflammatory process, A serie s of peptides, based on a conserved region ((48)YYWIGIRK(55)-NH2) of t he lectin domain of E-, L- and P-selectins, were analysed for their ab ility to block selectin-mediated cell adhesion in vitro, and neutrophi l infiltration into sites of inflammation in vivo, The peptides inhibi ted the adhesion of myeloid cells to recombinant forms of E- and P-sel ectin, The adhesion of myeloid cells to human endothelial cells, stimu lated to express E-selectin, was also inhibited by the peptides, Final ly, the peptides blocked the adhesion of lymphocytes, expressing L-sel ectin, to high endothelial venules in lymph nodes which contain the li gand for L-selectin, A clear structure-activity relationship was estab lished when peptides of different amino acid chain lengths were tested in these assays, Peptides lacking tyrosine residues (e.g. WIGIR-NH2) at their amino terminus were poor inhibitors of selectin-mediated cell adhesion ill vitro, The peptides that were found to be inhibitors of cell adhesion in vitro were also found to inhibit (up to 70%) neutroph il infiltration into sites of inflammation in a thioglycollate-induced peritonitis mouse model system, They also significantly reduced (>50% ) the migration of neutrophils into cytokine-treated skin. These resul ts strongly suggest that compounds based on these tyrosine-containing, selectin-derived peptides could be used as anti-inflammatory therapeu tic agents.