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

IL-4是一种T细胞衍生的淋巴因子，具有强大的调节作用 在人类单核细胞上。我们先前已经发现IL-4显著 抑制内毒素诱导的多种细胞因子的产生，包括IL-1 1、肿瘤坏死因子和白介素6；然而，目前尚不清楚白介素4如何抑制细胞因子 综合。确定IL-4是否通过一种途径抑制IL-1的表达 转录和/或转录后机制，我们评估了 脂多糖诱导的IL-1β消息的半衰期和转录速率 人单核细胞经IL-4处理后的前IL-1β基因。 尽管对照组和IL-4组的初始稳态IL-1mRNA水平。 经处理的单核细胞在接下来的2小时内是相似的 在内毒素刺激下，IL-1消息水平随后在 在IL-4处理的细胞中，这一比率明显更高。因此，IL-4没有 阻止了IL-1消息的初始表达，但确实加速了下调- 内毒素刺激单核细胞IL-1mRNA表达的调节最初的2-3个小时 滞后期可能是产生一种蛋白质所必需的(S) 这种抑制作用是因为处理后的蛋白质合成 环己亚胺抑制剂阻断了IL-1信息传递的显著减少 IL-4诱导的水平。核运行分析表明，IL-4 部分通过抑制IL-1基因转录，降低IL-1mRNA水平。 此外，信使核糖核酸半衰期研究表明IL-4也显著 增加IL-1消息在这些细胞中的周转率。一起， 这些发现表明，IL-4抑制人IL-1的产生 单核细胞通过抑制新的IL-1转录本的形成以及 通过降低IL-1消息的稳定性。此外，动力学研究表明， 抑制和放线菌亚胺阻断这一过程的事实表明 IL-4诱导或促进一种蛋白质的合成(S) 这些影响。鉴于IL-4抑制血管内皮细胞合成 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作用 以IL-1的过度或不受调节的表达为特征。

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.