Involvement of cytokines in human immunodeficiency virus-1 protein Tat and methamphetamine interactions in the striatum.
Involvement of cytokines in human immunodeficiency virus-1 protein Tat and methamphetamine interactions in the striatum.
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细胞因子参与人类免疫缺陷病毒 1 蛋白 Tat 和纹状体中甲基苯丙胺的相互作用。
DOI：
10.1016/j.expneurol.2006.01.009
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Maragos,WilliamF
中科院分区：
文献类型：
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作者：
Theodore,Shaji;Cass,WayneA;Maragos,WilliamF
人类免疫缺陷病毒-1 （HIV-1）感染大脑导致促炎细胞因子升高和纹状体炎症变化。与不滥用药物的hiv -1感染者相比，滥用包括精神兴奋剂甲基苯丙胺（MA）在内的药物的hiv -1感染者会出现更严重的脑炎和神经元损伤。在之前的研究中，我们证明了HIV-1蛋白Tat和MA通过破坏多巴胺能末端而相互作用，导致大鼠纹状体中多巴胺的损失增加。由于Tat和MA都能激活胶质细胞并诱导细胞因子的产生，我们利用细胞因子阵列研究了细胞因子在Tat和MA诱导的协同神经毒性中的作用。与生理盐水、Tat或MA相比，Tat + MA治疗4小时后单核细胞趋化蛋白（MCP-1）、白细胞介素-1α (IL-1α)和组织金属蛋白酶-1抑制剂（TIMP-1）水平显著升高。与生理盐水或MA相比，在Tat + MA后16小时，MCP-1和TIMP-1水平仍保持升高，但在此时间点与Tat治疗组没有差异。细胞因子诱导的中性粒细胞趋化因子-3 （cinc3）、纤毛神经营养因子（CNTF）和巨噬细胞炎症蛋白-3α (MIP-3α)也有微弱但显著的升高。在MCP-1基因缺陷的小鼠中，Tat和MA的相互作用被阻止，从而减弱了Tat + MA的神经毒性。我们的研究结果表明，HIV-1感染并发药物滥用可能会大大增加纹状体中的趋化因子水平，从而增加对多巴胺能系统的损害。
Human immunodeficiency virus-1 (HIV-1) infection of the brain causes elevation in pro-inflammatory cytokines and inflammatory changes in the striatum. HIV-1-infected individuals who also abuse drugs including the psychostimulant methamphetamine (MA) develop more severe encephalitis and neuronal damage compared to HIV-1-infected patients who do not abuse drugs. In previous studies, we demonstrated that the HIV-1 protein Tat and MA interacted to cause enhanced loss of dopamine in the rat striatum via the destruction of dopaminergic terminals. Since both Tat and MA activate glia and induce cytokine production, we investigated the role of cytokines in the synergistic neurotoxicity induced by Tat and MA using cytokine arrays. Significant increases in monocyte chemotactic protein (MCP-1), interleukin-1 alpha (IL-1α) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were noted 4 h following Tat + MA treatment compared to saline, Tat or MA. MCP-1 and TIMP-1 levels remained elevated 16 h after Tat + MA compared to saline or MA but were not different from the Tat-treated group at this time point. Weak, but significant elevations in cytokine-induced neutrophil chemoattractant-3 (CINC-3), ciliary neurotrophic factor (CNTF) and macrophage inflammatory protein-3 alpha (MIP-3α) were also noted with Tat + MA. The interaction of Tat and MA was prevented in mice genetically deficient in MCP-1 with a consequent attenuation of Tat + MA neurotoxicity. Our findings suggest that HIV-1 infection with concurrent drug abuse might profoundly increase chemokine levels in the striatum resulting in enhanced damage to the dopaminergic system.