Rabbi M F, Finnegan A, Al-Harthi L, Song S, Roebuck K A
Department of Immunology/Microbiology, Rush Presbyterian St. Luke's Medical School Chicago, Illinois, USA.
J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Dec 1;19(4):321-31. doi: 10.1097/00042560-199812010-00002.
Interleukin-10 (IL-10) is elevated in HIV-1-infected individuals and has been implicated in disease progression. We previously reported that IL-10 cooperates with tumor necrosis factor-alpha (TNF-alpha) to activate HIV-1 expression synergistically in acutely infected monocyte-derived macrophages and the chronically infected U1 promonocytic cell line. To determine whether IL-10 also cooperates with TNF-alpha to activate latent HIV-I expression in lymphocytes, we examined the effects of IL-10 on proviral expression in the chronically infected T-cell line, ACH-2. Although IL-10 inhibited HIV-1 expression acting alone, in combination with suboptimal concentrations of TNF-alpha, IL-10 increased HIV-1 steady-state mRNA expression and p24 core antigen production in ACH-2 cells. Interestingly, IL-10 concentrations that synergistically induced virus also maximally stimulated endogenous TNF-alpha expression, suggesting that cell-derived TNF-alpha may contribute to cytokine synergy. Transfection studies in ACH-2 cells indicated that IL-10 combined with TNF-alpha to activate the HIV-1 long terminal repeat (LTR). IL-10 also cooperated with TNF-alpha to activate HIV-1 LTR in 1G5 cells, a Jurkat T-cell line stably transfected with an LTR-dependent luciferase reporter gene. Pyrrolidine dithiocarbamate, a potent transcriptional inhibitor of the viral LTR, abrogated the cytokine responses in both U1 and ACH-2 cells, suggesting a common TNF-alpha-mediated transcriptional mechanism in these cell types despite their different modes of provirus latency. Taken collectively, these data suggest that IL-10 enhances suboptimal TNF-alpha activation of HIV-1 transcription in chronically infected T-cells at least in part through induction of endogenous TNF-alpha expression.
白细胞介素-10（IL-10）在HIV-1感染个体中水平升高，并与疾病进展有关。我们之前报道过，IL-10与肿瘤坏死因子-α（TNF-α）协同作用，在急性感染的单核细胞衍生巨噬细胞和慢性感染的U1前单核细胞系中激活HIV-1表达。为了确定IL-10是否也与TNF-α协同激活淋巴细胞中潜伏的HIV-1表达，我们检测了IL-10对慢性感染的T细胞系ACH-2中前病毒表达的影响。尽管IL-10单独作用时抑制HIV-1表达，但与次优浓度的TNF-α联合时，IL-10增加了ACH-2细胞中HIV-1稳态mRNA表达和p24核心抗原的产生。有趣的是，协同诱导病毒的IL-10浓度也最大程度地刺激了内源性TNF-α表达，表明细胞来源的TNF-α可能有助于细胞因子协同作用。ACH-2细胞中的转染研究表明，IL-10与TNF-α联合激活HIV-1长末端重复序列（LTR）。IL-10还与TNF-α协同激活1G5细胞中的HIV-1 LTR，1G5细胞是一种稳定转染LTR依赖性荧光素酶报告基因的Jurkat T细胞系。吡咯烷二硫代氨基甲酸盐是病毒LTR的有效转录抑制剂，可消除U1和ACH-2细胞中的细胞因子反应，表明尽管这些细胞类型的前病毒潜伏模式不同，但在这些细胞类型中存在共同的TNF-α介导的转录机制。总的来说，这些数据表明，IL-10至少部分通过诱导内源性TNF-α表达来增强慢性感染T细胞中次优TNF-α对HIV-1转录的激活。
