REGULATION OF INTERLEUKIN-1 BETA GENE EXPRESSION IN HUMAN MONOCYTES BY IL-4

IL-4对人单核细胞中白细胞介素1β基因表达的调节

• 批准号: 3804758
• 负责人: R P DONNELLY
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3804758
• 关键词: biological signal transduction; cell communication molecule; cycloheximide; gene expression; gene induction /repression; genetic transcription; human genetic material tag; human tissue; immunoregulation; interleukin 1; interleukin 4; lipopolysaccharides; messenger RNA; monocyte; nuclear runoff assay; protein biosynthesis; tissue /cell culture

IL-4 is a T cell-derived lymphokine that exerts potent regulatory effects on human monocytes. We have previously found that IL-4 significantly inhibits production of a number of LPS-inducible cytokines, including IL- 1, TNF and IL-6; however, it is not known how IL-4 suppresses cytokine synthesis. To determine whether IL-4 suppresses IL-1 expression by a transcriptional and/or posttranscriptional mechanism, we evaluated the half-life of LPS-induced IL-1beta message and transcriptional rate of the pro-IL-1beta gene in human monocytes following treatment with IL-4. Although the initial steady-state IL-1 mRNA levels in control and IL-4- treated monocytes were comparable during the first 2 hours following stimulation with LPS, IL-1 message levels subsequently decreased at a significantly greater rate in the IL-4-treated cells. Thus IL-4 did not prevent the initial expression of IL-1 message, but did accelerate down- regulation of IL-1 mRNA in LPS-stimulated monocytes. The initial 2-3 hour lag period may be necessary for production of a protein(s) which mediates this inhibitory effect because treatment with the protein synthesis inhibitor, cycloheximide, blocked the marked reduction of IL-1 message levels induced by IL-4. Nuclear run-on analyses demonstrated that IL-4 decreases IL-1 mRNA levels in part by repressing IL-1 gene transcription. Furthermore, mRNA half-life studies showed that IL-4 also significantly increases the rate of IL-1 message turnover in these cells. Together, these findings demonstrate that IL-4 inhibits IL-1 production in human monocytes by suppressing the formation of new IL-1 transcripts as well as by decreasing IL-1 message stability. In addition, the kinetics of inhibition and the fact that cycloheximide blocks this process suggest that IL-4 induces or enhances synthesis of a protein(s) which mediates these effects. In view of the fact that IL-4 inhibits synthesis of various proinflammatory cytokines, particularly IL-1, it may be worth evaluating the potential therapeutic effects of IL-4 in disease states characterized by excessive or unregulated expression of IL-1.

IL-4 是一种 T 细胞衍生的淋巴因子，具有有效的调节作用 在人类单核细胞上。 我们之前发现IL-4显着 抑制多种 LPS 诱导细胞因子的产生，包括 IL- 1、TNF和IL-6；然而，尚不清楚IL-4如何抑制细胞因子 合成。 确定 IL-4 是否通过以下方式抑制 IL-1 表达： 转录和/或转录后机制，我们评估了 LPS 诱导的 IL-1beta 信息的半衰期和转录率 IL-4 处理后人单核细胞中的 pro-IL-1beta 基因。 尽管对照和 IL-4- 中的初始稳态 IL-1 mRNA 水平 治疗后的前 2 小时内，处理过的单核细胞具有可比性 LPS 刺激后，IL-1 信息水平随后降低 IL-4处理的细胞中的比率显着更高。 因此IL-4不 阻止 IL-1 信息的初始表达，但确实加速了下调 LPS 刺激的单核细胞中 IL-1 mRNA 的调节。 最初的2-3小时 滞后期对于介导蛋白质的产生可能是必要的 这种抑制作用是因为蛋白质合成治疗 抑制剂放线菌酮可阻断 IL-1 信息的显着减少 IL-4 诱导的水平。 核连续分析表明 IL-4 部分通过抑制 IL-1 基因转录来降低 IL-1 mRNA 水平。 此外，mRNA 半衰期研究表明 IL-4 也显着 增加这些细胞中 IL-1 信息周转率。 一起， 这些发现表明 IL-4 抑制人体内 IL-1 的产生 通过抑制新 IL-1 转录物的形成以及 通过降低 IL-1 信息稳定性。 此外，动力学 抑制作用以及放线菌酮阻断这一过程的事实表明 IL-4 诱导或增强介导蛋白质的合成 这些影响。 鉴于IL-4抑制合成 各种促炎细胞因子，特别是 IL-1，可能值得 评估 IL-4 在疾病状态下的潜在治疗效果 其特征是 IL-1 过度或不受调节的表达。