INDUCTION OF IG C EPSILON & C GAMMA 1 BY IL4 & CD40L

IG C Epsilon 感应

• 批准号: 2887624
• 负责人: Janet M. Stavnezer
• 金额: $ 23.96万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887624
• 关键词: B lymphocyte; CD40 molecule; DNA binding protein; DNA footprinting; biological signal transduction; chimeric proteins; chromatin; crosslink; gene mutation; gene rearrangement; genetic promoter element; immunoglobulin E; immunoglobulin G; immunoglobulin genes; interleukin 4; laboratory mouse; nuclear factor kappa beta; nucleosomes; polymerase chain reaction; protein binding; tissue /cell culture; transcription factor; transfection

After immunization or infection, B cells undergo immunoglobulin (Ig) class switching, which results in expression of a new heavy chain constant region (C/H) region gene. Class switching allows the humoral immune response to adaptively respond to a variety of different infectious organisms to produce the best antibody for each pathogen. This proposal will investigate the mechanism of regulation of class switching to IgG1 and IgE, using the mouse a model system. This proposal will investigate the mechanism of regulation of class switching to IgG1 and IgE, using the mouse as a model system. Both IgG1 and IgE are produced in response to T dependent antigens, although IgG1 in much greater abundance that IgE. IgG1 in effective against bacterial, viral and nematode infections due to its ability to active complement and to bind to FcRgammaIII on macrophages, neutrophils, mast cells and NK cells. IgE helps to eliminate parasitic helminths, although it does not appear to be essential for this immune response and in industrial societies is generally more dangerous than protective, as it causes allergy, including asthma. Thus, the ability to increase IgG1 and decrease IgE responses would be useful medically. Numerous studies have established that transcription of the C/H gene to which cells will switch is induced prior to switching by cytokines and B cell activators, and that this transcription is required for class switching. This proposal is to investigate the mechanism of regulation of germline gamma1 and epsilon transcription by cytokines and B cell activators known to regulate class switching to IgG1 and IgE. The proposal will specifically investigate and compare the regulation of the germline gamma1 and epsilon transcripts by three transcription factors/families which are involved in induction of transcription by IL-4 and CD40 signaling: Stat6, NF-kappaB/Rel proteins, and b-Zip proteins. We have shown that Stat6 and NF-kappaB directly bind each other and have evidence suggesting this is the mechanism whereby IL-4 and CD40 signaling synergistically induce transcription. This proposal will directly address whether this binding is necessary for their synergy and analyze the mechanism of their interaction. A b-Zip binding site which binds Ap-1 is also required for the ability of Stat6 to induce transcription, but the requirement for the Ap-1 binding site is not understood. We will investigate whether this requirement is due to the inability of Stat6 to bind to chromatin in vivo in the absence of AP-1. The promoters for the gamma1 and epsilon germline transcripts have similar binding sites for Stat6, NF-kappaB and AP-1 (or for C/EBP), but these sites are differentially arranged. We will determine if it is the differential arrangement and/or different binding proteins at the b-Zip element which regulates their different responses to IL-4 and B cell activators.

免疫或感染后，B 细胞进行免疫球蛋白 (Ig) 分类 转换，导致新的重链常数的表达 区（C/H）区基因。类别转换允许体液免疫 适应性反应以适应各种不同的传染性 生物体针对每种病原体产生最佳抗体。这个提议 将研究类别转换为 IgG1 的调节机制 和 IgE，使用小鼠模型系统。本提案将调查 使用 IgG1 和 IgE 类别转换的调节机制 鼠标作为模型系统。 IgG1 和 IgE 都是响应 T 产生的 依赖抗原，尽管 IgG1 的丰度比 IgE 多得多。免疫球蛋白G1 因其具有抗细菌、病毒和线虫感染的功效 活性补体并结合巨噬细胞上的 FcRgammaIII 的能力， 中性粒细胞、肥大细胞和 NK 细胞。 IgE 有助于消除寄生虫 蠕虫，尽管它对于这种免疫似乎不是必需的 在工业社会中的反应通常比 具有保护作用，因为它会引起过敏，包括哮喘。因此，能够 增加 IgG1 并减少 IgE 反应在医学上是有用的。 大量研究已证实 C/H 基因的转录 哪些细胞将在转换之前由细胞因子和 B 诱导 细胞激活剂，并且这种转录是类所需的 交换。本提案旨在研究监管机制 细胞因子和 B 细胞的种系 gamma1 和 epsilon 转录 已知调节 IgG1 和 IgE 类别转换的激活剂。提案 将专门调查和比较生殖系的调控 三个转录因子/家族的 gamma1 和 epsilon 转录本 参与 IL-4 和 CD40 转录诱导 信号传导：Stat6、NF-kappaB/Rel 蛋白和 b-Zip 蛋白。我们有 表明Stat6和NF-kappaB直接相互结合并有证据 表明这是 IL-4 和 CD40 信号传导的机制 协同诱导转录。该提案将直接解决 这种结合对于它们的协同作用是否是必要的并分析 他们相互作用的机制。结合 Ap-1 的 b-Zip 结合位点是 Stat6 诱导转录的能力也是必需的，但是 Ap-1 结合位点的要求尚不清楚。我们将 调查此要求是否是由于 Stat6 无法 在没有 AP-1 的情况下与体内染色质结合。发起人为 gamma1 和 epsilon 种系转录物具有相似的结合位点 Stat6、NF-kappaB 和 AP-1（或 C/EBP），但这些位点是 差异化排列。我们将确定是否是差异 b-Zip 元件上的排列和/或不同的结合蛋白 调节它们对 IL-4 和 B 细胞激活剂的不同反应。