Plasmodium falciparum-infected erythrocytes increase intercellular adhesion molecule 1 expression on brain endothelium through NF-kappaB.
Plasmodium falciparum-infected erythrocytes increase intercellular adhesion molecule 1 expression on brain endothelium through NF-kappaB.
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DOI：
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发表时间：
2006
影响因子：
3.1
通讯作者：
A. Tripathi;D. Sullivan;M. Stins
中科院分区：
文献类型：
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作者：
A. Tripathi;D. Sullivan;M. Stins
恶性疟原虫感染红细胞(PF-IRBC)在毛细血管后脑内皮细胞中的隔离是脑型疟疾(CM)发病机制的一个标志。人脑微血管内皮细胞(HBMEC)上细胞间黏附分子-1(ICAM-1)的表达增加与PF-IRBC的黏附相关。ICAM-1表达增加的潜在机制尚未明确。因此，我们研究了PF-IRBC作用于体外培养的HBMEC后ICAM-1表达的机制。模型的超微结构特征证实存在通过PF-IRBC旋钮和HBMEC微绒毛突起的附着。PF-IRBC诱导HBMEC上ICAM-1的表达呈剂量和时间依赖性增加，这种表达是人脑血管内皮细胞所特有的，而对人脐静脉内皮细胞则不存在。通过表面胰酶消化和分级，证实膜相关的PF-IRBC蛋白和寄生虫来源的可溶性因子都参与了ICAM-1表达的增加。应用转录因子NF-kappaB的特异性抑制剂和免疫细胞化学方法显示，PF-IRBC暴露可诱导HBMEC中核因子-kappaB的核转位，这与ICAM-1的表达有关。此外，抑制活性氧还可降低PF-IRBC诱导的HBMEC上ICAM-1的表达。寄生虫诱导的ICAM-1表达解释了该分子在死后CM脑样本的脑内皮细胞上的定位。通过增加ICAM-1的表达，PF-IRBC可能增加它们的封存，从而使CM永久化。
Sequestration of Plasmodium falciparum-infected erythrocytes (Pf-IRBC) in postcapillary brain endothelium is a hallmark of cerebral malaria (CM) pathogenesis. There is a correlation between adherent Pf-IRBC and increased expression of intercellular cell adhesion molecule 1 (ICAM-1), which is also a receptor for Pf-IRBC on human brain microvascular endothelial cells (HBMEC). The underlying mechanism for the increased ICAM-1 expression has not been clearly defined. Therefore, we investigated the mechanisms of ICAM-1 expression on isolated HBMEC after exposure to Pf-IRBC. Ultrastructural characterization of the model confirmed that there was attachment through both Pf-IRBC knobs and HBMEC microvillus protrusions. Pf-IRBC induced a dose- and time-dependent increase in ICAM-1 expression on HBMEC that was specific for human brain endothelium and was not observed with human umbilical vein endothelium. Involvement of both membrane-associated Pf-IRBC proteins and parasite-derived soluble factors with the increase in ICAM-1 expression was demonstrated by surface trypsinization and fractionation. Pf-IRBC exposure induced nuclear translocation of NF-kappaB in HBMEC, which was linked to ICAM-1 expression, as shown by use of specific inhibitors of the transcription factor NF-kappaB and immunocytochemistry. In addition, inhibition of reactive oxygen species decreased Pf-IRBC-induced ICAM-1 expression on HBMEC. Parasite-induced ICAM-1 expression explains the localization of this molecule on brain endothelium in postmortem CM brain samples. By increasing ICAM-1 expression, Pf-IRBC may increase their sequestration, thereby perpetuating CM.