Ehrenreich H, Rieckmann P, Sinowatz F, Weih K A, Arthur L O, Goebel F D, Burd P R, Coligan J E, Clouse K A
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1993 May 15;150(10):4601-9.
Monocytes/macrophages play a critical role in the pathogenesis of HIV infection, both as targets for virus replication and as sources of production of multifunctional cytokines. Endothelins, peptides with potent vasoconstricting activities originally isolated from endothelial cells, are also produced and secreted by macrophages in a manner similar to that of other cytokines. In an attempt to explore the potential role of endothelins in HIV-infection, we investigated the effect of the HIV-1 envelope glycoprotein, glycoprotein 120, on monocytic endothelin-1 production. This glycoprotein has been identified as a potent stimulator of monokines such as TNF-alpha and IL-6, which have been implicated as potential mediators of HIV-encephalopathy. We found that glycoprotein 120, similar to LPS, stimulates the secretion of endothelin-1, as well as TNF-alpha, from macrophages in a concentration-dependent manner. Using reverse transcriptase polymerase chain reaction, we found that circulating monocytes in HIV-infected individuals show a distinct expression of the endothelin-1 gene that is not detectable in healthy controls, indicating chronic activation of this gene in HIV-infection. In addition, cerebral macrophages in patients with HIV-encephalopathy were strongly positive for endothelin. Thus, monocytic endothelins appear to be stimulated during HIV infection. Their potent vasoactive properties render them potential candidates for mediating alterations in the cerebral perfusion pattern associated with the AIDS dementia complex.
单核细胞/巨噬细胞在HIV感染的发病机制中起关键作用，既是病毒复制的靶细胞，又是多功能细胞因子的产生来源。内皮素是最初从内皮细胞中分离出的具有强力血管收缩活性的肽类，巨噬细胞也以与其他细胞因子类似的方式产生并分泌内皮素。为了探索内皮素在HIV感染中的潜在作用，我们研究了HIV-1包膜糖蛋白糖蛋白120对单核细胞内皮素-1产生的影响。这种糖蛋白已被确定为单核因子如TNF-α和IL-6的强力刺激物，而这些单核因子被认为是HIV脑病的潜在介质。我们发现，糖蛋白120与LPS相似，以浓度依赖的方式刺激巨噬细胞分泌内皮素-1以及TNF-α。使用逆转录聚合酶链反应，我们发现HIV感染个体的循环单核细胞显示出内皮素-1基因的独特表达，而在健康对照中无法检测到，这表明该基因在HIV感染中被慢性激活。此外，HIV脑病患者的脑巨噬细胞内皮素呈强阳性。因此，单核细胞内皮素在HIV感染期间似乎受到刺激。它们强大的血管活性特性使其成为介导与艾滋病痴呆综合征相关的脑灌注模式改变的潜在候选者。
