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Table of Contents
Vol. 22, No. 5-6, 2008
Issue release date: December 2008
Section title: Original Paper
Cell Physiol Biochem 2008;22:745–756
(DOI:10.1159/000185558)

Neuroinflammation Activates Mdr1b Efflux Transport Through NFκB: Promoter Analysis in BBB Endothelia

Yu C. · Argyropoulos G. · Zhang Y. · Kastin A.J. · Hsuchou H. · Pan W.
Pennington Biomedical Research Center, Baton Rouge, LA 70808
email Corresponding Author

Weihong Pan, M.D., Ph.D.

Pennington Biomedical Research Center

6400 Perkins Road, Baton Rouge, LA 70808 (USA)

Tel. +1-225-763-2707, Fax: +1-225-763-0261

E-Mail weihong.pan@pbrc.edu

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Abstract

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 NFκB nuclear translocation; and (3) the NFκB 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 NFκB to nuclear DNA from RBE4 cells was shown by electrophoretic mobility shift assay and chromatin immunoprecipitation assays. Conclusion: NFκB mediates TNF-induced upregulation of mdr1b promoter activity, illustrating how inflammation activates BBB efflux transport.

© 2008 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Accepted: July 11, 2008
Published online: December 09, 2008
Issue release date: December 2008

Number of Print Pages: 12
Number of Figures: 0
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

For additional information: http://www.karger.com/CPB


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