Inhibition of adhesion of human neutrophils and eosinophils to P-selectin by the sialyl Lewis antagonist TBC1269: preferential activity against neutrophil adhesion in vitro.
BACKGROUND
Leukocyte rolling on vascular endothelium is mediated by selectins and their carbohydrate-containing counterligands. The tetrasaccharide sialyl Lewis(x) (sLe(x)) binds to all 3 selectins, so compounds that mimic sLe(x) are potential antagonists.


OBJECTIVE
Our purpose was to examine the ability of the sLe(x) mimetic TBC1269 to inhibit binding of human neutrophils and eosinophils to P-selectin.


METHODS
Expression of the primary P-selectin ligand, P-selectin glycoprotein ligand-1 (PSGL-1), was examined on neutrophils and eosinophils, and their adhesion to immobilized P-selectin was examined under both static and dynamic conditions in the presence and absence of TBC1269.


RESULTS
Neutrophils and eosinophils expressed PSGL-1, with eosinophils expressing about twice as much as neutrophils. In the absence of TBC1269, both cell types adhered avidly to P-selectin under static and dynamic conditions. For neutrophils, preincubation of P-selectin-coated plates with TBC1269 (1 to 1000 microgram/mL) resulted in concentration-dependent decreases in neutrophil adhesion, with significant inhibition seen at concentrations >/=100 microgram/mL. Eosinophil adhesion to P-selectin was more refractory to inhibition by TBC1269 and was only partially inhibited at the highest concentration tested (1000 microgram/mL). Two structurally related control compounds, TBC1900 and TBC746, had no effect when tested at similar concentrations.


CONCLUSIONS
These data indicate that an sLe(x) mimetic can exhibit cell type-specific differences in potencies with respect to antagonism of P-selectin adhesion. Although this may in part be the result of differences in PSGL-1 expression, the discrepancy in potencies may also be due to other differences, including carbohydrate composition and binding affinity of PSGL-1.
Davenpeck
K L
KL
Division of Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Berens
K L
KL
Dixon
R A
RA
Dupre
B
B
Bochner
B S
BS
D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D004804:Eosinophils / Q000166:cytology*; D006801:Humans; D007983:Lewis Blood Group Antigens; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000494:pharmacology*; D009504:Neutrophils / Q000166:cytology*; D009844:Oligosaccharides / Q000037:antagonists & inhibitors*; D019007:P-Selectin / Q000187:drug effects / Q000494:pharmacology*; D000080506:Sialyl Lewis X Antigen
D018927:Anti-Asthmatic Agents; D001713:Biphenyl Compounds; D007983:Lewis Blood Group Antigens; D008362:Mannosides; D009844:Oligosaccharides; D019007:P-Selectin; D000080506:Sialyl Lewis X Antigen; C108700:bimosiamose disodium; D008358:Mannose