Ameliorating skin-homing receptors on malignant T cells with a fluorosugar analog of N-acetylglucosamine:: P-selectin ligand is a more sensitive target than E-selectin ligand
Ameliorating skin-homing receptors on malignant T cells with a fluorosugar analog of N-acetylglucosamine:: P-selectin ligand is a more sensitive target than E-selectin ligand
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DOI：
10.1038/sj.jid.5700364
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发表时间：
2006-09-01
影响因子：
6.5
通讯作者：
Dimitroff, Charles J.
中科院分区：
文献类型：
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作者：
Descheny, Leyla;Gainers, Madeliene E.;Dimitroff, Charles J.
E-和P-选择素配体的表达是T细胞进入皮肤所必需的。唾液酸刘易斯X部分对于配体活性是关键的，并且在恶性皮肤归巢T细胞上升高。我们假设这些糖基化是治疗皮肤淋巴瘤相关的皮肤嗜性的可选择的靶点。在这项研究中，我们分析了一种新的N-乙酰葡萄糖胺（GlcNAc）的4-氟类似物对恶性皮肤归巢T细胞表达的E-和P-选择素配体的疗效。我们还通过对比P-选择素糖蛋白配体-1（PSGL-1）与CD 43表达的唾液酸化O-聚糖对唾液酸化刘易斯X表达的影响，检查了4-F-GlcNAc（2-乙酰氨基-1，3，6-三-O-乙酰基-4-脱氧-4-氟-D-吡喃葡萄糖）作用的特异性。使用平行板流动分析，我们发现4-F-GlcNAc对P-选择素配体活性的抑制比对E-选择素配体活性的抑制强5倍。为了确定赋予E-和P-选择素配体活性的糖基化是否受到抑制，我们分别分析了唾液酸刘易斯X和唾液酸岩藻糖基化核心2 O-聚糖（CHO-131抗原）的表达。我们发现，4-F-GlcNAc处理导致PSGL-1上唾液酸化刘易斯X和CHO-131抗原表达的剂量依赖性消除，而CD 43上的唾液酸化O-聚糖受到的影响最小。这些结果表明，4-F-GlcNAc治疗可以选择性地下调P-选择素配体活性，并可能防止皮肤淋巴瘤的皮肤传播。
Expression of E- and P-selectin ligands is required for T cell entry into skin. Sialyl Lewis X moieties are critical for ligand activity and are elevated on malignant skin-homing T cells. We hypothesize that these glycosylations are selectable targets for treating the dermal tropism associated with cutaneous lymphomas. In this study, we analyzed the efficacy of a novel 4-fluorinated analog of N-acetylglucosamine (GlcNAc) on E- and P-selectin ligands expressed by malignant skin-homing T cells. We also examined the specificity of 4-F-GlcNAc (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose) action by contrasting the effects on sialyl Lewis X expression displayed by P-selectin glycoprotein ligand-1 (PSGL-1) with sialylated O-glycans expressed by CD43. Using parallel-plate flow analysis, we found that 4-F-GlcNAc elicited 5-fold more potent inhibition on P-selectin ligand activity than on E- selectin ligand activity. To determine whether glycosylations conferring E- and P-selectin ligand activities were inhibited, we analyzed the expression of sialyl Lewis X and sialyl-fucosylated core 2 O-glycan (CHO-131 antigen), respectively. We found that 4-F-GlcNAc treatment resulted in dose-dependent ablation of sialyl Lewis X and CHO-131 antigen expression on PSGL-1, whereas sialylated O-glycans on CD43 were minimally affected. These results indicate that 4-F-GlcNAc treatment can selectively downregulate the P-selectin ligand activity and potentially prevent dermal dissemination of cutaneous lymphomas.