Extracellular HIV-1 Tat up-regulates expression of matrix metalloproteinase-9 via a MAPK-NF-κB dependent pathway in human astrocytes
Extracellular HIV-1 Tat up-regulates expression of matrix metalloproteinase-9 via a MAPK-NF-κB dependent pathway in human astrocytes
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DOI：
10.3858/emm.2009.41.2.011
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发表时间：
2009-02-28
影响因子：
12.8
通讯作者：
Park, Jinseu
中科院分区：
文献类型：
--
作者：
Ju, Sung Mi;Song, Ha Yong;Park, Jinseu
单核细胞向中枢神经系统的浸润是艾滋病相关脑炎和痴呆中炎症事件的早期步骤之一。所选基质金属蛋白酶（MMP）如MMP-9的活性增加损害血脑屏障的完整性，导致单核细胞向CNS中的浸润增强。在这项研究中，我们研究了HIV-1达特对CRT-MG人星形胶质瘤细胞MMP-9表达的影响。用HIV-1达特蛋白处理CRT-MG细胞显著增加MMP-9的蛋白水平，如通过Western印迹分析、酶谱分析和ELISA所测量的。RT-PCR分析显示，HIV-1达特蛋白处理CRT-MG细胞后，MMP-9的mRNA水平显著升高。用NF-κ B抑制剂预处理CRT-MG细胞导致Tat诱导的MMP-9蛋白和mRNA表达减少。用MAPK抑制剂预处理CRT-MG细胞抑制Tat诱导的MMP-9表达。此外，HIV-1 Tat诱导的MMP-9的表达被TNF-α的中和显著抑制，而不是IL-1 β和IL-6。综上所述，我们的结果表明，HIV-1达特可以通过MAPK-NF-κ B依赖机制以及塔特诱导的星形胶质细胞TNF-α的产生上调MMP-9的表达。
The infiltration of monocytes into the CNS represents one of the early steps to inflammatory events in AIDS-related encephalitis and dementia. Increased activity of selected matrix metalloproteinases (MMPs) such as MMP-9 impairs the integrity of blood-brain barrier leading to enhanced monocyte infiltration into the CNS. In this study, we examined the effect of HIV-1 Tat on the expression of MMP-9 in CRT-MG human astroglioma cells. Treatment of CRT-MG cells with HIV-1 Tat protein significantly increased protein levels of MMP-9, as measured by Western blot analysis, zymography and an ELISA. Treatment of CRT-MG cells with HIV-1 Tat protein markedly increased mRNA levels of MMP-9, as analyzed by RT-PCR. Pretreatment of CRT-MG cells with NF-kappa B inhibitors led to decrease in Tat-induced protein and mRNA expression of MMP-9. Pretreatment of CRT-MG cells with MAPK inhibitors suppressed Tat-induced MMP-9 expression. Furthermore, HIV-1 Tat-induced expression of MMP-9 was significantly inhibited by neutralization of TNF-alpha, but not IL-1 beta and IL-6. Taken together, our results indicate that HIV-1 Tat can up-regulate expression of MMP-9 via MAPK-NF-kappa B-dependent mechanisms as well as Tat-induced TNF-alpha production in astrocytes.