Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease.
Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease.
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DOI：
10.1084/jem.176.6.1703
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发表时间：
1992-12-01
期刊：
影响因子：
--
通讯作者：
Volsky DJ
中科院分区：
文献类型：
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作者：
Genis P;Jett M;Bernton EW;Boyle T;Gelbard HA;Dzenko K;Keane RW;Resnick L;Mizrachi Y;Volsky DJ
人类免疫缺陷病毒(HIV)感染脑巨噬细胞和星形胶质细胞增殖是HIV诱导的中枢神经系统(CNS)疾病的主要特征。这些观察表明，神经胶质细胞的相互作用参与了疾病。在一个检测这一过程的实验系统中，我们发现HIV感染的单核细胞和星形胶质细胞共培养时会释放高水平的细胞因子和花生四烯酸代谢产物，从而导致神经元毒性。HIV-1ADA感染的单核细胞与人星形胶质细胞(星形细胞瘤、神经胶质细胞和原代人星形胶质细胞)共同培养，通过耦合反转录-聚合酶链式反应、酶联免疫吸附试验和生物活性检测肿瘤坏死因子(TNF-α)和白介素1β(IL-1β)的合成。细胞因子的诱导是选择性的，细胞特异性的，并与花生四烯酸代谢产物的诱导有关。未产生肿瘤坏死因子-β、白介素1-α、白介素6、干扰素-α和干扰素-γ。经高效液相分离后，大量检测到白三烯B4、白三烯D4、脂氧素A4和血小板活化因子，并与细胞因子活性相关。花生四烯酸级联反应的特异性抑制剂显着降低细胞因子的反应，提示这些因子之间存在调节关系。将HIV感染的单核细胞与神经母细胞瘤或内皮细胞，或HIV感染的单核细胞液，蔗糖梯度浓缩的病毒颗粒，以及多聚甲醛固定或冻融的HIV感染的单核细胞共培养到星形胶质细胞上，均未能诱导细胞因子和神经毒素。这表明细胞反应需要可行的单核细胞-星形胶质细胞相互作用。在共培养前，在感染HIV的单核细胞中加入放线菌素D或放线菌亚胺，可将肿瘤坏死因子-α的水平降低2.5倍。综上所述，这些结果表明，与HIV中枢神经系统疾病相关的神经毒性部分是通过细胞因子和花生四烯酸代谢产物介导的，这些代谢产物是在HIV感染的脑巨噬细胞和星形胶质细胞之间的细胞间相互作用中产生的。
Human immunodeficiency virus (HIV) infection of brain macrophages and astroglial proliferation are central features of HIV-induced central nervous system (CNS) disorders. These observations suggest that glial cellular interactions participate in disease. In an experimental system to examine this process, we found that cocultures of HIV-infected monocytes and astroglia release high levels of cytokines and arachidonate metabolites leading to neuronotoxicity. HIV-1ADA-infected monocytes cocultured with human glia (astrocytoma, neuroglia, and primary human astrocytes) synthesized tumor necrosis factor (TNF-alpha) and interleukin 1 beta (IL-1 beta) as assayed by coupled reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and biological activity. The cytokine induction was selective, cell specific, and associated with induction of arachidonic acid metabolites. TNF-beta, IL-1 alpha, IL-6, interferon alpha (IFN-alpha), and IFN-gamma were not produced. Leukotriene B4, leukotriene D4, lipoxin A4, and platelet-activating factor were detected in large amounts after high-performance liquid chromatography separation and correlated with cytokine activity. Specific inhibitors of the arachidonic cascade markedly diminished the cytokine response suggesting regulatory relationships between these factors. Cocultures of HIV-infected monocytes and neuroblastoma or endothelial cells, or HIV-infected monocyte fluids, sucrose gradient-concentrated viral particles, and paraformaldehyde-fixed or freeze-thawed HIV-infected monocytes placed onto astroglia failed to induce cytokines and neuronotoxins. This demonstrated that viable monocyte-astroglia interactions were required for the cell reactions. The addition of actinomycin D or cycloheximide to the HIV-infected monocytes before coculture reduced, > 2.5-fold, the levels of TNF-alpha. These results, taken together, suggest that the neuronotoxicity associated with HIV central nervous system disorders is mediated, in part, through cytokines and arachidonic acid metabolites, produced during cell-to- cell interactions between HIV-infected brain macrophages and astrocytes.