REGULATION OF IL-1 AND IL-1 RECEPTOR ANTAGONIST EXPRESSION BY IL-4

IL-4对IL-1和IL-1受体拮抗剂表达的调节

• 批准号: 3792490
• 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/3792490
• 关键词: cytokine receptors; gene expression; human tissue; inhibitor /antagonist; interleukin 1; interleukin 4; interleukin 6; leukocyte activation /transformation; lipopolysaccharides; protein biosynthesis

In this project, we evaluated the effects of the T cell-derived lymphokine IL-4, on the ability of human monocytes to express IL-1 and the IL-1 receptor antagonist (IL-lra), a new member of the IL-1 gene family. Activation of human monocytes with lipopolysaccharide (LPS) induces coordinate expression of a number of proinflammatory cytokine genes, including IL-lalpha, IL-1beta, TNF-alpha, IL-6 and IL-8. IL-4 inhibits expression of these genes in monocytes, suggesting that it may be an important physiologic regulator of cytokine production. We have previously shown that IL-4 reduces steady-state mRNA levels for IL-lbeta in human monocytes by decreasing both IL-lbeta transcription and the half -life of newly formed IL-lbeta mRNA transcripts. We have now extended these findings to show that IL-4 similarly accelerates the turnover of IL-6 mRNA in LPS-stimulated monocytes. However, this inhibition of cytokine expression and dramatic increase in the decay rate of cytokine mRNA does not extend to all LPS-inducible genes because IL-4 treatment did not inhibit expression or accelerate turnover of mRNA for IL-lra in the same cells. Although IL-lbeta and IL-lra are both LPS-inducible genes, they displayed distinct temporal patterns of expression. Peak steady-state mRNA levels for IL-lra lagged significantly behind that of IL-1beta, suggesting a possible endogenous mechanism for limiting IL-1 biologic activity. Furthermore, although IL-4 suppressed expression of both IL-1beta and IL-6, it upregulated synthesis of IL-lra mRNA and protein. Thus, IL-4 inhibits production of the proinflammatory cytokine IL-1beta while increasing synthesis of IL-lra in activated human monocytes. This pathway may have evolved to provide a mechanism by which the host can effectively regulate both the production and activity of this potent proinflammatory mediator. Furthermore, these findings provide additional support for the potential therapeutic use of IL-4 in disease states which are characterized by excessive production of IL-1.

在这个项目中，我们评估了T细胞衍生的 淋巴因子IL-4对人单核细胞表达IL-1的能力， IL-1受体拮抗剂（IL-1 ra）是IL-1基因的新成员 家人 用脂多糖（LPS）激活人单核细胞 诱导多种促炎细胞因子协同表达 基因，包括IL-1 α、IL-1 β、TNF-α、IL-6和IL-8。 IL-4 抑制单核细胞中这些基因的表达，这表明它可能 是细胞因子产生的重要生理调节剂。 我们有 先前显示IL-4降低IL-1 β的稳态mRNA水平 通过降低IL-1 β的转录和IL-1 β的一半， - 新形成的IL-1 β mRNA转录物的寿命。 我们现在已经扩大了 这些发现表明IL-4同样加速了 LPS刺激的单核细胞中的IL-6 mRNA。 然而，这种抑制 细胞因子表达和细胞因子衰减率的显著增加 mRNA并不延伸到所有LPS诱导的基因，因为IL-4处理 并不抑制IL-1 ra的表达或加速IL-1 ra mRNA的周转。 同样的细胞。 虽然IL-1 β和IL-1 ra都是LPS诱导的， 基因，他们表现出不同的时间模式的表达。 峰值 IL-1 ra的稳态mRNA水平显著落后于 IL-1 β，表明限制IL-1的可能内源性机制 生物活性。 此外，虽然IL-4抑制了 IL-1 β和IL-6均可上调IL-1 ra mRNA的合成， 蛋白 因此，IL-4抑制促炎细胞因子的产生 IL-1 β同时增加活化人IL-1 ra的合成 单核细胞 这条通路可能已经进化为提供一种机制， 宿主可以有效地调节 这种强有力的促炎介质。 此外，这些发现 为IL-4在以下疾病中的潜在治疗用途提供了额外的支持： 以IL-1的过度产生为特征的疾病状态。