INTERLEUKIN 4 (IL-4)

白细胞介素 4 (IL-4)

• 批准号: 6098948
• 负责人: William Paul
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 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/6098948
• 关键词: T cell receptor; T lymphocyte; biological signal transduction; cell differentiation; cytokine receptors; gene expression; gene mutation; genetically modified animals; interferon gamma; interleukin 4; laboratory mouse; leukocyte activation /transformation; receptor binding; regulatory gene; tissue /cell culture

Interleukin-4 (IL-4) is a multifunctional type I cytokine. Among its most important functions are determining the production of certain immunoglobulin classes, particularly IgE through the regulation of immunoglobulin class switching, and the determination of the differentiation of na?ve CD4+ T cells into TH2 cells. The work covered under this project has been concerned with key biologic functions of IL-4, the means through which IL-4 producing cells appear, and the molecular basis through which IL-4 signaling is accomplished. The IL-4 receptor (R) is a heterodimer consisting of the IL-4 Ra chain and the gc chain. Distinct domains of the receptor largely control IL-4 mediated growth and gene activation. Growth depends upon an IL-4Ra domain centering on Y497; phosphorylated Y497 acts as a docking site for a series of PTB-domain-containing proteins including IRS-1, IRS-2, Shc, and FRIP, a newly identified IL-4 receptor interacting protein. IRS-1, IRS-2 and Shc mediate their function by acting as adapter molecules that recruit pathways leading to growth and resistance to apoptosis. FRIP is a PTB-domain containing protein that appears to inhibit the RAS pathway through it capacity to bind to RAS-GAP and to recruit it to the vicinity of activated RAS. FRIP has recently been shown to be phosphorylated in response to IL-2 , IL-3 and insulin. It is also phosphorylated in response to T cell receptor engagement, although it is not established whether this is direct or indirect. FRIP is hyperphosphorylated in anergic AE7 cells and, in its ability to block the RAS pathway, may play a role in induction or maintenance of the anergic state. IL-4-mediated gene activation and differentiation, such as immunoglobulin class switching and development of na?ve T cells into TH2 cells depend upon the activation of Stat6; such activation is controlled by a more distal portion of the IL-4 Ra chain containing three tyrosines, each one of which, when phosphorylated, appears to be a Stat-6 binding site. These Stat6 sites can be moved to another part of the receptor where they continue to mediate their function of inducing IL-4-specific gene activation. Recent studies indicate that the level of expression of IL-4Ra chain is controlled by a process of phosphorylation/ dephosphorylation. Indeed, mice lacking the phosphatase SHP-1 are defective in IL-4 Ra expression, presumably because of tonic phosphorylation of key tyrosines in the receptor cytosolic domain. Development of naive T cells into IL-4-producing cells is dependent upon IL-4 itself. IL-4Ra chain knockout mice display a major impairment in the development of TH2-type immune responses in response to infection with Nippostrongylus brasiliensis. There does appear to be a potential pathway of development of TH2 cells independent of IL-4 (or IL-13) and of Stat6. It is revealed by the study of BCL6 knockout mice, which develop a severe cardiac and lung inflammatory disease characterized by the production of TH2 cytokines. BCL6 is a transcriptional repressor that interacts with genetic elements similar to those recognized by Stat6 and thus potentially inhibits Stat6; in the absence of BCL6 , TH2 differentiation may occur spontaneously. Indeed, mice that are knockouts for both BCL6 and Stat6 or BCL6 and IL-4 continue to develop the TH2-based inflammatory responses although their peripheral T cells continue to require IL-4 in order to develop into TH2 cells. The development of naive TH precursor cells into TH1 and TH2 cells is a highly regulated process, with the acquisition of IL-4 and IFNg-producing activities being independently controlled. Fully differentiated TH1 cells fail to acquire IL-4-producing capacity even when cultured with antigen in the presence of IL- 4. It has now been shown that fully differentiated TH1 cells display a desensitized IL-4R. IL-4 fails to elicit STAT-6 phosphorylation in such cells. Interestingly, these cells also are deficient in IRS-2, as are cells of STAT-6 KO mice that have been stimulated in vitro in with IL-4. Thus, the induction of the major growth regulatory substrate phosphorylated in response to IL-4 is under the control of STAT-6, explaining how the gene activation function of the IL-4 receptor plays a role in controlling growth. These experiments provide a framework in which to understand the mechanisms through which IL-4 determines the biologic characteristics of immune responses and to identify biochemical steps in its function that may be suitable for the development of antagonists of agonists that could aid in the development of drugs for a variety of allergic, autoimmune, infectious and inflammatory diseases.

白介素4（IL-4）是多功能的I型 细胞因子。它最重要的功能是确定 产生某些免疫球蛋白类别，尤其是IgE 通过调节免疫球蛋白类切换， 确定Na？ve CD4+ T细胞为Th2的分化 细胞。该项目涵盖的工作一直关注 IL-4的关键生物学功能，IL-4的均值 产生细胞以及IL-4的分子基础 信号已完成。 IL-4受体（R）是异二聚体 由IL-4 RA链和GC链组成。不同的领域 受体在很大程度上控制IL-4介导的生长和基因 激活。增长取决于IL-4RA领域的中心 Y497;磷酸化的Y497充当一系列的对接场所 包括IRS-1，IRS-2，SHC和 FRIP，一种新鉴定的IL-4受体相互作用蛋白。 IRS-1， IRS-2和SHC通过充当适配器来介导其功能 募集导致生长和抵抗力的分子 凋亡。 FRIP是一种含有蛋白质的PTB域 抑制通过IT结合RAS间隙的IT能力的RAS途径 并将其招募到激活的Ras附近。 FRIP最近有 被证明是响应IL-2，IL-3和 胰岛素。它也响应T细胞受体而被磷酸化 订婚，尽管尚未确定这是直接的还是 间接。 FRIP在Anergic AE7细胞中过度磷酸化，并在 它阻止RAS途径的能力可能在归纳或 维持厌食状态。 IL-4介导的基因激活和 分化，例如免疫球蛋白类切换和 Na？ve t细胞到Th2细胞中的发展取决于 激活STAT6；这种激活受到更远端的控制 IL-4 RA链的一部分，其中包含三个酪氨酸，每个酪氨酸 当磷酸化时，它似乎是Stat-6结合位点。 这些STAT6站点可以移至受体的另一部分 他们继续调解诱导的功能 IL-4特异性基因激活。最近的研究表明该水平 IL-4RA链的表达由 磷酸化/去磷酸化。确实，老鼠缺乏 磷酸酶SHP-1在IL-4 RA表达中有缺陷，大概是 由于受体中关键酪氨酸的滋补磷酸化 胞质结构域。幼稚的T细胞发展到 产生IL-4的细胞取决于IL-4本身。 IL-4RA链 淘汰小鼠在开发中表现出重大损害 Th2型免疫反应响应感染 nippostrongylus brasiliensis。似乎有潜力 Th2细胞开发的途径独立于IL-4（或 IL-13）和STAT6。它通过Bcl6敲除的研究揭示了 小鼠，患有严重的心脏和肺部炎症性疾病 以Th2细胞因子的产生为特征。 Bcl6是一个 与遗传元件相互作用相似的转录阻遏物 对于STAT6认可的人，因此可能抑制STAT6；在 可能没有BCl6，可能会发生Th2分化 自发。确实，Bcl6和 Stat6或Bcl6和IL-4继续开发基于Th2的 炎症反应尽管其周围T细胞继续 需要IL-4才能发展成Th2细胞。发展 天真的Th前体细胞进入Th1和Th2细胞是高度 经过IL-4和IFNG生产的监管过程 活动是独立控制的。完全分化的TH1 即使培养，细胞也无法获得IL-4产生能力 抗原在IL-4的存在下。现在已经证明 完全分化的Th1细胞显示脱敏的IL-4R。 IL-4失败 在此类细胞中引起Stat-6磷酸化。有趣的是，这些 细胞也缺乏IRS-2，Stat-6 KO小鼠的细胞也是如此 用IL-4在体外刺激的。因此，诱导 在主要的生长调节基材中磷酸化 对IL-4的响应在Stat-6的控制之下，解释了如何 IL-4受体的基因激活功能在 控制增长。这些实验提供了一个框架 要了解IL-4的机制 确定免疫反应的生物学特征和对 确定其功能中可能适合的生化步骤 发展激动剂的拮抗剂，可以帮助 开发各种过敏性自身免疫性的药物 传染性和炎症性疾病。