Regulation of Il-4 in Cells Involved in Allergic Disease

过敏性疾病细胞中 IL-4 的调节

• 批准号: 7003654
• 负责人: VINCENZO CASOLARO
• 金额: $ 31.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7003654
• 关键词: Regulation; Il; Cells; Involved; Allergic

DESCRIPTION (provided by applicant): 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 Th1 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-4locus 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 ofCP2 and NF-kappaB in IL-4 transcription, will provide a basis for studies of the expression and 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.

描述（由申请人提供）：IL-4在Th 2细胞和嗜碱性粒细胞中表达。IL-4的表达增加是过敏性疾病的既定标志。最近的研究已经允许鉴定其表达或激活与IL-4的Th 2限制性表达相关的核因子（NF）。我们已经确定了两个NF，CP 2和NF-κ B，对IL-4和IL-2转录产生不同的影响。我们发现，CP 2和NF-κ B种类p65和p50在Th 1和Th 2细胞中差异表达，并通过与其他NF的复杂相互作用直接与IL-4启动子相互作用来调节转录。我们假设这些蛋白质在IL-4基因的激活中发挥相关作用。我们将研究：1）CP 2在IL-4基因激活中的作用（目的1）。我们将分析CP 2在Th细胞和嗜碱性粒细胞中的表达和功能，以及CP 2缺失、功能受损或强制表达对IL-4产生的影响。2)通过NF-κ B分子种类调节IL-4的意义（目的2）。我们的研究结果表明，p65-p50的平衡直接影响IL-4在Th细胞和嗜碱性粒细胞的表达。我们将研究这些细胞中p65的表达，以及选择性阻断p65对转基因小鼠细胞因子诱导的影响。3)CP 2和p50激活IL-4基因的机制（目的3）。通过体外和体内蛋白质-DNA相互作用的分析，我们将研究CP 2和p50与IL-4启动子和远端调控元件的功能相互作用及其对IL-4位点重塑和可及性的影响。我们将研究它们与辅助因子阴阳1、Bcl-3和NF-IL 6相互作用的意义。研究IL-4的调节机制对于了解过敏性疾病的分子基础至关重要。通过明确CP 2和NF-κ B在IL-4转录中的作用，该方法将为研究这些因子在过敏性炎症中的表达和功能提供基础，并确定新的、特异性的免疫调节分子靶点。鉴于CP 2和NF-κ B参与多种宿主细胞和病毒基因的转录，我们的研究结果也将对这些蛋白质在健康和疾病基因表达调控中的意义和功能的定义产生更广泛的影响。