Regulation of Il-4 in Cells Involved in Allergic Disease

IL-4在Th2细胞和嗜碱性粒细胞中表达。IL-4的高表达是一个公认的标志 过敏性疾病。最近的研究使得核因子(NF)的表达成为可能 或激活与Th2限制的IL-4表达有关。我们鉴定了两种核因子，CP2和CP2 核因子-kappaB，对IL-4和IL-2转录有不同的影响。我们证明了CP2和 核因子-kappaB基因p65和p50在Th1和Th2细胞中的差异表达并调节 通过与其他核因子的复杂相互作用，直接与IL-4启动子相互作用而转录。我们 假设这些蛋白质在IL-4基因的激活中发挥相关作用。我们将调查：1) CP2在IL-4基因激活中的作用(目标1)。我们将分析CP2在Th中的表达和功能 细胞和嗜碱性粒细胞及CP2耗竭、功能障碍或强迫表达对IL-4的影响 制作。2)核因子-kappaB分子物种对IL-4调节的意义(目标2)。我们的发现 提示p65-p50平衡直接影响Th细胞和嗜碱性粒细胞IL-4的表达。我们会去看看 在这些细胞中p65的表达，以及选择性阻断p65对细胞因子诱导的影响。 转跨显性阻遏基因的小鼠。3)CP2和Cp2激活IL-4基因的机制 P50(目标3)。通过体外和体内蛋白质-DNA相互作用的分析，我们将研究 CP2和p50与IL-4启动子和远端调控元件的相互作用及其对IL-4的影响 轨迹重塑和可达性。我们将研究它们与辅因子阴的相互作用的意义 Yang 1、Bcl3和NFIL6。剖析IL-4的调节机制对 了解过敏性疾病的分子基础。建议的方法是通过定义 CP2和NF-kappaB在IL-4转录中的表达，将为研究其表达和功能提供基础 这些因素在过敏性炎症中的作用，并确定新的、特异的分子靶点 免疫调节。鉴于CP2和NF-kappaB参与了多种宿主的转录 细胞和病毒基因，我们的结果也将在定义意义上有更广泛的意义 以及这些蛋白在健康和疾病中调节基因表达的功能。

IL-4 is expressed in Th2 cells and basophils. Increased expression of IL-4 is an established hallmark of allergic diseases. Recent studies have allowed the identification of nuclear factors (NF) whose expression or activation are associated with Th2-restricted expression of IL-4. We have identified two NF, CP2 and NF-kappaB, exerting diverging effects on IL-4 and IL-2 transcription. We show that CP2 and the NF-kappaB species p65 and p50 are differentially expressed in Thl and Th2 cells and regulate transcription by directly interacting with the IL-4 promoter via a complex interplay with other NF. We hypothesize that these proteins play a relevant role in activation of the IL-4 gene. We will investigate: 1) The role of CP2 in IL-4 gene activation (Aim 1). We will analyze the expression and function of CP2 in Th cells and basophils and the effect of CP2 depletion, functional impairment or forced expression on IL-4 production. 2) The significance of IL-4 regulation by NF-kappaB molecular species (Aim 2). Our findings implicate that the p65-p50 balance directly affects IL-4 expression in Th cells and basophils. We will look at the expression of p65 in these cells, and the impact of selective p65 blockade on cytokine induction in mice transgenic for a transdominant repressor. 3) The mechanism of IL-4 gene activation by CP2 and p50 (Aim 3). By in vitro and in vivo analysis of protein-DNA interactions we will study the functional interaction of CP2 and p50 with the IL-4 promoter and distal regulatory elements and their impact on IL-4 locus remodeling and accessibility. We will study the significance of their interaction with the cofactors Yin Yang 1, Bcl-3 and NF-IL6. Dissecting the mechanisms of IL-4 regulation is of crucial importance to understanding the molecular basis of allergic disease. The proposed approach, by defining the roles of CP2 and NF-kappaB in IL-4 transcription, will provide a basis for studies of the expression ana function of these factors in allergic inflammation, and identify novel, specific molecular targets for immunomodulation. Given the involvement of CP2 and NF-kappaB in transcription of a diverse host of cellular and viral genes, our results will also have broader implications in the definition of the significance and function of these proteins in the regulation of gene expression in health and disease.