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

在这个项目中，我们评估了T细胞来源的效果 淋巴因子IL-4对人单核细胞表达IL-1和 IL-1基因的新成员--IL-1受体拮抗剂(IL-LRA) 一家人。内毒素对人单核细胞的激活作用 诱导多种促炎细胞因子的协同表达 基因，包括IL-α、IL-1β、TNF-α、IL-6和IL-8。白介素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因子。我们有 先前研究表明，IL-4可降低IL-1β的稳态mRNA水平 在人单核细胞中，通过同时减少IL-1β转录和一半 -新形成的IL-1βmRNA转录本的寿命。我们现在已经延长了 这些发现表明，IL-4类似地加速了细胞的周转 内毒素刺激的单核细胞表达IL-6mRNA。然而，这种抑制 细胞因子的表达与细胞因子衰减率的急剧增加 由于IL-4治疗，mRNA不会延伸到所有内毒素诱导的基因 不抑制IL-LRA的mRNA表达或促进其周转 同样的细胞。尽管IL-1β和IL-1RA都是内毒素诱导的 基因，它们表现出不同的时间表达模式。尖峰 IL-LRA的稳态mRNA水平明显落后于 IL-1β，提示了限制IL-1的可能内源性机制 生物活动。此外，尽管IL-4抑制了血管内皮生长因子的表达。 IL-1β和IL-6均上调IL-LRA mRNA和IL-6的合成 蛋白。因此，IL-4抑制促炎细胞因子的产生 IL-1β同时增加活化人IL-1RA的合成 单核细胞。这一途径可能已经进化成提供一种机制，通过这种机制 寄主可以有效地调节植物的生产和活动。 这种强有力的促炎介质。此外，这些发现 为IL-4的潜在治疗用途提供更多支持 以IL-1过度产生为特征的疾病状态。

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.