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) 是一种多功能 I 型 细胞因子。其最重要的功能之一是确定 生产某些免疫球蛋白类别，特别是 IgE 通过调节免疫球蛋白类别转换，以及 确定幼稚 CD4+ T 细胞分化为 TH2 细胞。该项目涵盖的工作涉及 IL-4 的关键生物学功能，IL-4 发挥作用的途径 产生细胞的出现，以及 IL-4 产生的分子基础 信令完成。 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 受体的变化很大程度上控制 IL-4 介导的生长和基因 激活。生长依赖于以 IL-4Ra 结构域为中心的结构域 Y497；磷酸化的 Y497 充当一系列的对接位点 含有 PTB 结构域的蛋白质，包括 IRS-1、IRS-2、Shc 和 FRIP，一种新发现的 IL-4 受体相互作用蛋白。国税局-1， IRS-2 和 Shc 通过充当适配器来调节其功能 招募导致生长和抵抗的途径的分子 细胞凋亡。 FRIP 是一种含有 PTB 结构域的蛋白质，似乎 通过与 RAS-GAP 结合的能力抑制 RAS 通路 并将其招募到激活的 RAS 附近。 FRIP 最近 研究表明，IL-2、IL-3 和 IL-2 会导致磷酸化 胰岛素。它还响应 T 细胞受体而被磷酸化 参与，尽管尚不清楚这是直接参与还是 间接。 FRIP 在无反应性 AE7 细胞中过度磷酸化，并且在 它阻断 RAS 途径的能力，可能在诱导或 维持无反应状态。 IL-4介导的基因激活和 分化，例如免疫球蛋白类别转换和 幼稚 T 细胞发育为 TH2 细胞取决于 激活Stat6；这种激活是由更远端的控制的 IL-4 Ra链的一部分含有三个酪氨酸，每个酪氨酸为 当磷酸化时，它似乎是 Stat-6 结合位点。 这些 Stat6 位点可以移动到受体的另一部分 他们继续发挥诱导功能 IL-4 特异性基因激活。最近的研究表明，水平 IL-4Ra链的表达受以下过程控制 磷酸化/去磷酸化。事实上，小鼠缺乏 据推测，磷酸酶 SHP-1 在 IL-4 Ra 表达中存在缺陷 由于受体中关键酪氨酸的强直性磷酸化 胞质结构域。幼稚 T 细胞发育成 IL-4 产生细胞依赖于 IL-4 本身。 IL-4Ra链 基因敲除小鼠的发育受到严重损害 TH2型免疫反应对感染的反应 巴西圆线虫。似乎确实有潜力 TH2细胞的发育途径不依赖于IL-4（或 IL-13) 和 Stat6。 BCL6敲除研究揭示 小鼠，出现严重的心脏和肺部炎症疾病 其特点是产生 TH2 细胞因子。 BCL6 是 与类似遗传元件相互作用的转录抑制因子 那些被 Stat6 识别并因此可能抑制 Stat6 的物质；在 BCL6缺失，TH2分化可能发生 自发地。事实上，同时敲除 BCL6 和 Stat6或BCL6和IL-4继续开发基于TH2的 尽管它们的外周T细胞继续发生炎症反应 需要IL-4才能发育成TH2细胞。发展历程 将初始 TH 前体细胞转化为 TH1 和 TH2 细胞是一个高度 调节过程，获得产生 IL-4 和 IFNg 的 活动受到独立控制。全差异化TH1 即使在培养时，细胞也无法获得产生 IL-4 的能力 在 IL-4 存在的情况下与抗原结合。现在已经表明 完全分化的 TH1 细胞显示出脱敏的 IL-4R。 IL-4失败 引发此类细胞中的 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 已在体外用 IL-4 刺激。因此，归纳 主要生长调节底物磷酸化 对 IL-4 的反应受到 STAT-6 的控制，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 了解 IL-4 的机制 决定免疫反应的生物学特征并 确定其功能中可能适合的生化步骤 开发激动剂的拮抗剂，有助于 开发针对多种过敏、自身免疫、 传染性和炎症性疾病。