Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells

被引:105
作者
András, IE
Pu, H
Tian, J
Deli, MA
Nath, A
Hennig, B
Toborek, M
机构
[1] Univ Kentucky, Dept Surg, Lexington, KY 40536 USA
[2] Biol Res Ctr, H-6701 Szeged, Hungary
[3] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA
[4] Univ Kentucky, Coll Agr, Lexington, KY 40536 USA
关键词
blood-brain barrier; brain endothelial cells; HIV-1; dementia; signal transduction; tight junctions;
D O I
10.1038/sj.jcbfm.9600115
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Exposure of brain microvascular endothelial cells (BIVIEC) to human immunodeficiency virus-1 (HIV-1) Tat protein can decrease expression and change distribution of tight junction proteins, including claudin-5. Owing to the importance of claudin-5 in maintaining the blood-brain barrier (BBB) integrity, the present study focused on the regulatory mechanisms of Tat-induced alterations of claudin-5 mRNA and protein levels. Real-time reverse-transcription-polymerase chain reaction revealed that claudin-5 mRNA was markedly diminished in BMEC exposed to Tat. However, U0126 (an inhibitor of mitogen-activated protein kinase kinase1/2, MEK1/2) protected against this effect. In addition, inhibition of the vascular endothelial growth factor receptor type 2 (VEGFR-2) by SU1498, phosphatidylinositol-3 kinase (PI-3 K) by LY294002, nuclear factor-kappa B (NF-kappa B) by peptide SN50, and intracellular calcium by BAPTA/AM partially prevented Tat-mediated alterations in claudin-5 protein levels and immunoreactivity patterns. In contrast, inhibition of protein kinase C did not affect claudin-5 expression in Tat-treated cells. The present findings indicate that activation of VEGFR-2 and multiple redox-regulated signal transduction pathways are involved in Tat-induced alterations of claudin-5 expression. Because claudins constitute the major backbone of tight junctions, the present data are relevant to the disturbances of the BBB in the course of HIV-1 infection.
引用
收藏
页码:1159 / 1170
页数:12
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