Human immunodeficiency virus type 1 Tat and methamphetamine affect the release and activation of matrix-degrading proteinases
Human immunodeficiency virus type 1 Tat and methamphetamine affect the release and activation of matrix-degrading proteinases
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DOI：
10.1080/13550280490261699
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发表时间：
2004-01-01
影响因子：
3.2
通讯作者：
Nath, A
中科院分区：
文献类型：
--
作者：
Conant, K;St Hillaire, C;Nath, A
人类免疫缺陷病毒（HIV）痴呆（HIVD）与中枢神经系统（CNS）内激活的单核细胞数量增加有关，这是一种在叠加药物滥用的情况下可能更显著的病理特征。单核细胞可以将HIV转运到大脑，此外，活化和/或感染的单核细胞已被证明释放许多有效的神经毒素。尽管负责增加单核细胞进入CNS的机制是多种的，但血脑屏障（BBB）降解基质金属蛋白酶（MMPs）可能发挥重要作用。目前的研究调查了HIV-1编码的蛋白质达特和滥用药物甲基苯丙胺对脑源性细胞MMP释放的影响。还研究了MMPs的激活剂尿激酶纤溶酶原激活物（uPA）的释放。用达特或甲基苯丙胺刺激混合的人神经元/星形胶质细胞培养物，并通过酶联免疫吸附测定（ELISA）和/或明胶底物酶谱法分析上清液。结果表明，达特和甲基苯丙胺增加MMP-1从这些培养物的释放。达特还增加活性MMP-2的上清液水平。此外，达特和甲基苯丙胺均刺激MMP激活剂uPA的释放，并且以对百日咳毒素抑制敏感的方式。总之，这些结果表明，在HIVD，达特和甲基苯丙胺可能有助于中枢神经系统炎症刺激增加释放和/或激活基质降解蛋白酶通过机制，包括Gi/Go偶联信号。这些结果也表明了甲基苯丙胺使用加速HIVD的潜在机制。
Human immunodeficiency virus (HIV) dementia (HIVD) is associated with an increase in the number of activated monocytes within the central nervous system (CNS), a pathological feature that may be more remarkable in the setting of superimposed substance abuse. Monocytes may transport HIV to the brain, and, moreover, activated and/or infected monocytes have been shown to release a number of potent neurotoxins. Although the mechanisms responsible for the increase in the CNS ingress of monocytes are multiple, blood-brain barrier (BBB)-degrading matrix metalloproteinases ( MMPs) are likely to play an important role. The current study investigates the effects of the HIV-1-encoded protein Tat, and the drug of abuse methamphetamine, on MMP release from brain derived cells. The release of urokinase plasminogen activator (uPA), an activator of MMPs, was also investigated. Mixed human neuron/astrocyte cultures were stimulated with Tat or methamphetamine, and supernatants were analyzed by enzyme-linked immunosorbent assay ( ELISA) and/or gelatin substrate zymography. Results showed that Tat and methamphetamine increased the release of MMP-1 from these cultures. Tat also increased supernatant levels of active MMP-2. In addition, both Tat and methamphetamine stimulated the release of the MMP activator uPA, and in a manner that was sensitive to inhibition with pertussis toxin. Together, these results suggest that in HIVD, Tat and methamphetamine may contribute to CNS inflammation by stimulating increased release and/or activation of matrix-degrading proteinases through mechanisms that include Gi/Go-coupled signaling. These results also suggest potential mechanism for acceleration of HIVD with methamphetamine use.