Fine S M, Maggirwar S B, Elliott P R, Epstein L G, Gelbard H A, Dewhurst S
Department of Medicine, University of Rochester Medical Center, NY 14642, USA.
J Neuroimmunol. 1999 Mar 1;95(1-2):55-64. doi: 10.1016/s0165-5728(98)00267-7.
HIV-1 infection of the central nervous system can cause severe neurologic disease although only microglial cells and brain macrophages are susceptible to productive viral infection. Substances secreted by infected cells are thought to cause disease indirectly. Tumor necrosis factor alpha (TNF-alpha) is one candidate neurotoxin and is upregulated during HIV-1 infection of the brain, likely via activation of the transcription factor NF-kappaB. We used the proteasome inhibitors, MG132 and ALLN (N-acetyl-Leu-Leu-Norleucinal), to inhibit NF-kappaB activation in primary human fetal microglia (PHFM) and primary monocyte derived-macrophages, and showed that they could block TNF-alpha release stimulated by lipopolysaccharide (LPS) or TNF-alpha. In addition, we performed electrophoretic mobility shift analysis and determined that in microglia, the p50/p65 heterodimer of NF-kappaB is activated by LPS stimulation, and is inhibited by MG132. Thus, blockade of NF-kappaB activation in microglia in vitro can decrease production of TNF-alpha and may prove to be a novel strategy for treating HIV-1 dementia.
尽管只有小胶质细胞和脑巨噬细胞易受有 productive 的病毒感染，但人类免疫缺陷病毒 1 型（HIV-1）感染中枢神经系统可导致严重的神经疾病。受感染细胞分泌的物质被认为间接导致疾病。肿瘤坏死因子α（TNF-α）是一种候选神经毒素，在 HIV-1 脑感染期间可能通过转录因子 NF-κB 的激活而上调。我们使用蛋白酶体抑制剂 MG132 和 ALLN（N-乙酰亮氨酰-亮氨酰-正亮氨酸）抑制原代人胎儿小胶质细胞（PHFM）和原代单核细胞衍生巨噬细胞中的 NF-κB 激活，并表明它们可阻断脂多糖（LPS）或 TNF-α 刺激的 TNF-α 释放。此外，我们进行了电泳迁移率变动分析，并确定在小胶质细胞中，NF-κB 的 p50/p65 异二聚体被 LPS 刺激激活，并被 MG132 抑制。因此，体外阻断小胶质细胞中的 NF-κB 激活可降低 TNF-α 的产生，可能被证明是治疗 HIV-1 痴呆的一种新策略。
