G-CSF induces E-selectin ligand expression on human myeloid cells
G-CSF induces E-selectin ligand expression on human myeloid cells
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DOI：
10.1038/nm1470
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发表时间：
2006-10-01
期刊：
影响因子：
82.9
通讯作者：
Sackstein, Robert
中科院分区：
文献类型：
--
作者：
Dagia, Nilesh M.;Gadhoum, Samah Z.;Sackstein, Robert
临床使用G-CSF可导致血管和炎症并发症（1-7）。为了研究这些效应的分子基础，我们分析了G-CSF动员的人外周血白细胞（ML）与炎症（TNF-α刺激）血管内皮的粘附。在小鼠炎症模型中，在生理流动条件下使用平行板测定和活体显微镜检查的研究均表明，与未动员的（天然）血液白细胞相比，ML参与了与内皮细胞的粘附相互作用，由显着增加的E-选择素受体-配体相互作用介导。生物化学研究表明，ML表达有效的E-选择素配体HCELL（参考文献8）和另一种先前未识别的类似于65-kDa E-选择素配体的配体，并具有增强水平的编码糖基转移酶（ST 3GaIIIV、FucT-IV和FucT-VII）的转录本，这些转录本赋予与E-选择素配体活性相关的聚糖修饰。酶处理和生理结合试验表明，HCELL和类似于65-kDa的E-选择素配体显著促进观察到的G-CSF诱导的髓样细胞粘附到发炎的内皮。在体外用药代动力学相关浓度的G-CSF处理正常人骨髓细胞（9，10）导致这两种分子的表达增加，与编码相关糖基转移酶的转录物增加和E-选择素结合增强一致。这些发现为G-CSF在诱导骨髓细胞上的E-选择素配体中的作用提供了直接证据，从而为G-CSF并发症的病理生物学提供了机制性见解。
Clinical use of G-CSF can result in vascular and inflammatory complications(1-7). To investigate the molecular basis of these effects, we analyzed the adherence of G-CSF-mobilized human peripheral blood leukocytes (ML) to inflamed (TNF-alpha - stimulated) vascular endothelium. Studies using parallel plate assays under physiologic flow conditions and intravital microscopy in a mouse inflammation model each showed that ML take part in heightened adhesive interactions with endothelium compared to unmobilized (native) blood leukocytes, mediated by markedly increased E-selectin receptor-ligand interactions. Biochemical studies showed that ML express the potent E-selectin ligand HCELL (ref. 8) and another, previously unrecognized similar to 65-kDa E-selectin ligand, and possess enhanced levels of transcripts encoding glycosyltransferases (ST3GaIIIV, FucT-IV and FucT-VII) conferring glycan modifications associated with E-selectin ligand activity. Enzymatic treatments and physiologic binding assays showed that HCELL and the similar to 65-kDa E-selectin ligand contribute prominently to the observed G-CSF-induced myeloid cell adhesion to inflamed endothelium. Treatment of normal human bone marrow cells with a pharmacokinetically relevant concentration of G-CSF in vitro(9,10) resulted in increased expression of these two molecules, coincident with increased transcripts encoding pertinent glycosyltransferases and heightened E-selectin binding. These findings provide direct evidence for a role of G-CSF in the induction of E-selectin ligands on myeloid cells, thus providing mechanistic insight into the pathobiology of G-CSF complications.