Inhibition of adhesion of human neutrophils and eosinophils to P-selectin by the sialyl Lewisx antagonist TBC1269:: Preferential activity against neutrophil adhesion in vitro

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:105

Article

Davenpeck, KL ; Berens, KL ; Dixon, RAF ; Dupre, B ; Bochner, BS

关键词: eosinophils;    neutrophils;    adhesion;    P-selectin;    PSGL-1;    antagonist;    glycomimetic;    sialyl Lewis(x);   

DOI  :  10.1067/mai.2000.105121

来源: Elsevier

【 摘 要 】

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, Tn 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 mu g/mL) resulted in concentration-dependent decreases in neutrophil adhesion, with significant inhibition seen at concentrations greater than or equal to 100 mu g/mL. Eosinophil adhesion to P-selectin was more refractory to inhibition by TBC1269 and was only partially inhibited at the highest concentration tested (1000 mu g/mL). Two structurally related control compounds, TBC1900 and TBC746, had no effect when tested at similar concentrations. Conclusion: These data indicate that an sLe(x) mimetic can exhibit fell 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.

【 授权许可】

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