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首页> 外文期刊>Cellular Physiology and Biochemistry >Neuroinflammation Activates Mdr1b Efflux Transport Through NF kappa B: Promoter Analysis in BBB Endothelia
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Neuroinflammation Activates Mdr1b Efflux Transport Through NF kappa B: Promoter Analysis in BBB Endothelia

机译：神经炎症激活通过NFκB的Mdr1b外排转运：BBB内皮细胞的启动子分析

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Background/aims: Although it is known that drug delivery across the blood-brain barrier (BBB) may be hampered by efflux transport activity of the multidrug resistance (mdr) gene product P-glycoprotein, it is not clear how inflammation regulates efflux transporters. In rat brain endothelial (RBE4) cells of BBB origin, the proinflammatory cytokine TNF mainly induced transcriptional upregulation of mdr1b, and to a lesser extent mdr1a, resulting in greater efflux of the substrates. This study further determines the mechanisms by which TNF activates mdr1b promoter activity. Methods/Results: Luciferase reporter assays and DNA binding studies show that (1) maximal basal promoter activity was conferred by a 476 bp sequence upstream to the mdr1b transcriptional initiation site; (2) TNF induced upregulation of promoter activity by NF kappa B nuclear translocation; and (3) the NF kappa B binding site of the mdr1b promoter was solely responsible for basal and TNF-activated gene transcription, whereas the p53 binding site was not involved. Binding of the p65 subunit of NF kappa B to nuclear DNA from RBE4 cells was shown by electrophoretic mobility shift assay and chromatin immunoprecipitation assays. Conclusion: NF kappa B mediates TNF-induced upregulation of mdr1b promoter activity, illustrating how inflammation activates BBB efflux transport.
机译：背景/目的：尽管已知跨多药耐药性（mdr）基因产物P-糖蛋白的外排转运活性可能会阻碍跨血脑屏障（BBB）的药物输送，但尚不清楚炎症如何调节外排转运蛋白。在BBB来源的大鼠脑内皮（RBE4）细胞中，促炎细胞因子TNF主要诱导mdr1b的转录上调，而在较小程度上降低了mdr1a的转录，导致底物的外排更大。这项研究进一步确定了TNF激活mdr1b启动子活性的机制。方法/结果：荧光素酶报告基因分析和DNA结合研究表明：（1）最大的基础启动子活性是由mdr1b转录起始位点上游的476 bp序列赋予的; （2）TNF通过NFκB核移位诱导启动子活性上调; （3）mdr1b启动子的NFκB结合位点仅负责基础和TNF激活的基因转录，而p53结合位点不参与。通过电泳迁移率迁移分析和染色质免疫沉淀分析显示了NFκB的p65亚基与RBE4细胞的核DNA结合。结论：NFκB介导TNF诱导的mdr1b启动子活性上调，说明炎症如何激活BBB外排转运。

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