Proinflammatory synergism of ethanol and HIV-1 Tat protein in brain tissue
Proinflammatory synergism of ethanol and HIV-1 Tat protein in brain tissue
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DOI：
10.1016/j.expneurol.2004.06.007
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发表时间：
2005-01-01
影响因子：
5.3
通讯作者：
Toborek, M
中科院分区：
文献类型：
--
作者：
Flora, G;Pu, H;Toborek, M
人类免疫缺陷病毒1型（HIV-1）达特蛋白是一种有效的病毒复制反式激活因子。它从HIV感染的细胞中主动释放，并已显示出诱导细胞损伤作用。酒精滥用是HIV感染的一个危险因素，我们假设酒精和达特可能以相加或协同的方式相互作用，影响分子过程，从而导致其毒性作用。为了研究这种可能性，我们研究了两次腹腔注射乙醇的影响（EtOH，各3 g/kg，间隔16 h）和单次脑内注射达特（25 μ g/穆尔注入右侧海马，在第一次注射EtOH后12小时注射）对细胞氧化应激的产生，氧化还原应答转录因子的DNA结合活性，以及诱导小鼠脑海马和纹状体中的炎性基因。与对照动物相比，用EtOH加达特处理导致两个脑区域中活性氧的产生增加。此外，与单独使用达特或EtOH的效果相比，在注射达特和EtOH的小鼠中，两个脑区中的核因子-κ B（NF-κ B）和CREB以及海马中的SP-1的DNA结合活性更明显。在研究的炎症基因中，在注射EtOH加达特的动物中，IL-1 β和MCP-1的诱导增强。这些结果表明，达特和乙醇可以交叉放大其细胞效应，导致大脑中氧化还原调节的炎症通路的改变。这种促炎性刺激的增强可能进一步导致酗酒的HIV感染患者的CNS病理学。(C)2004年由Elsevier Inc.出版
Human immunodeficiency virus type 1 (HIV-1) Tat protein is a potent transactivator of viral replication. It is actively released from HIV-infected cells and has been shown to induce cell injury effects. Alcohol abuse is a risk factor of HIV infection and we hypothesize that alcohol and Tat may interact in an additive or synergistic fashion to influence molecular processes which can contribute to their toxic effects. To study this possibility, we investigated the effects of two intraperitoneal injections of ethanol (EtOH, 3 g/kg each, 16 h apart) and a single intracerebral injection of Tat (25 mug/mul into the right hippocampus, injected 12 h after the first EtOH injection) on generation of cellular oxidative stress, DNA binding activity of redox-responsive transcription factors, and induction of inflammatory genes in the hippocampus and corpus striatum of mouse brain. As compared to control animals, treatment with EtOH plus Tat resulted in increased production of reactive oxygen species in both brain regions. In addition, DNA binding activities of nuclear factor-kappaB (NF-kappaB) and CREB in both brain regions and SP-1 in the hippocampus were more pronounced in mice injected with Tat plus EtOH as compared to the effects of Tat or EtOH alone. Among studied inflammatory genes, induction of IL-1beta and MCP-1 was potentiated in animals injected with EtOH plus Tat. These results indicate that Tat and EtOH can cross-amplify their cellular effects, leading to alterations of redox-regulated inflammatory pathways in the brain. Such potentiation of proinflammatory stimulation may further contribute to CNS pathology in HIV-infected patients who are alcohol abusers. (C) 2004 Published by Elsevier Inc.