Inhibition of adhesion of human neutrophils and eosinophils to P-selectin by the sialyl Lewisx antagonist TBC1269:: Preferential activity against neutrophil adhesion in vitro
Inhibition of adhesion of human neutrophils and eosinophils to P-selectin by the sialyl Lewisx antagonist TBC1269:: Preferential activity against neutrophil adhesion in vitro
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DOI：
10.1067/mai.2000.105121
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发表时间：
2000-04-01
影响因子：
14.2
通讯作者：
Bochner, BS
中科院分区：
文献类型：
--
作者：
Davenpeck, KL;Berens, KL;Bochner, BS
背景：白细胞在血管内皮上滚动是由选择素及其含碳水化合物的反配体介导的。四糖sialyl Lewis(x) （sLe(x)）与所有3种选择素结合，因此模拟sLe(x)的化合物是潜在的拮抗剂。目的：我们的目的是研究sLe(x)模拟物TBC1269抑制人中性粒细胞和嗜酸性粒细胞与p -选择素结合的能力。方法：检测p -选择素初级配体p -选择素糖蛋白配体1 （PSGL-1）在中性粒细胞和嗜酸性粒细胞上的表达，并在TBC1269存在和不存在的静态和动态条件下检测其对固定p -选择素的粘附。结果：中性粒细胞和嗜酸性粒细胞表达PSGL-1，嗜酸性粒细胞的表达量约为中性粒细胞的两倍，在TBC1269缺失的情况下，两种细胞在静态和动态条件下都对p -选择素有强烈的粘附。对于中性粒细胞，用TBC1269 （1 ~ 1000 μ g/mL）对p选择素包被的板进行预孵育，导致中性粒细胞粘附量呈浓度依赖性下降，浓度大于或等于100 μ g/mL时明显抑制。TBC1269对嗜酸性粒细胞粘附p -选择素的抑制作用较弱，在最高浓度（1000 μ g/mL）下仅部分抑制。两种结构相关的对照化合物TBC1900和TBC746在相似浓度下测试时没有影响。结论：这些数据表明，sLe(x)模拟物在p -选择素粘附拮抗方面表现出不同类型的特异性。虽然这可能部分是由于PSGL-1表达的差异，但效力的差异也可能是由于其他差异，包括PSGL-1的碳水化合物组成和结合亲和力。
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.