INTERLEUKIN 4 (IL-4)

白细胞介素4(IL-4)是一种多功能的I型 细胞因子。它最重要的功能之一是确定 某些免疫球蛋白类的产生，特别是IgE 通过调节免疫球蛋白类的转换，以及 幼稚的CD_4~+T细胞向TH2分化的测定 细胞。本项目所涵盖的工作一直关注 IL-4的关键生物学功能，IL-4通过的途径 产生细胞，以及IL-4通过的分子基础 信令已完成。IL-4受体(R)是一种异源二聚体 由IL-4Ra链和GC链组成。不同的域 受体在很大程度上控制着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 Y497；磷酸化的Y497作为一系列 含PTB结构域的蛋白包括IRS-1、IRS-2、Shc和 FRIP是一种新发现的IL-4受体相互作用蛋白。IRS-1， IRS-2和Shc通过充当适配器来调节其功能 分子招募导致生长和抵抗的途径 细胞凋亡。FRIP是一种含有PTB结构域的蛋白质，它似乎 抑制RAS途径与RAS-GAP结合的能力 并将其招募到激活的RAS附近。弗里普最近 被证明是对IL-2，IL-3和 胰岛素。它也被T细胞受体磷酸化。 参与，尽管还不能确定这是直接的还是 间接的。FRIP在无能AE7细胞中过度磷酸化，在 它阻断RAS途径的能力，可能在诱导或 无能状态的维持。IL-4介导的基因激活和 分化，如免疫球蛋白类转换和 幼稚T细胞向TH2细胞的发育依赖于 STAT6的激活；这种激活由更远端的 IL-4Ra链的一部分，含有三种酪氨酸，每一种 当被磷酸化时，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 在那里他们继续调解他们诱导的功能 IL-4特异性基因激活。最近的研究表明， IL-4ra链的表达受一个过程的控制 磷酸化/去磷酸化。事实上，老鼠缺乏 推测磷酸酶SHP-1在IL-4Ra的表达上存在缺陷 由于受体中关键酪氨酸的紧张性磷酸化 胞液结构域。幼稚T细胞发育为 产生IL-4的细胞依赖于IL-4本身。IL-4Ra链 基因敲除小鼠在发育过程中表现出重大的损害 丙型肝炎病毒感染后的Th2型免疫应答 巴西拟圆线虫。看起来确实有潜力 非IL-4(或)的TH2细胞发育途径 IL-13)和STAT6。BCL6基因敲除的研究揭示了这一点 小鼠，发展成严重的心脏和肺炎性疾病 以产生TH2细胞因子为特征。Bcl6是一种 与类似的遗传元件相互作用的转录抑制物 被Stat6识别并因此潜在地抑制Stat6的那些； 可能发生BCL6、TH2的缺失分化 自然而然地。事实上，BCL6和BCL6基因都被敲除的小鼠 STAT6或BCL6和IL-4继续开发基于TH2的 炎症反应，尽管他们的外周T细胞继续 需要IL-4才能发育成TH2细胞。最新进展 将幼稚的TH前体细胞转化为TH1和TH2细胞是一种高度 调节过程，获得IL-4和产生IFNG 活动受到独立控制。全分化TH1 细胞即使在培养时也无法获得产生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细胞表现出不敏感的IL-4R。IL-4失败 在这类细胞中诱导STAT-6的磷酸化。有趣的是，这些 细胞也缺乏IRS-2，STAT-6KO小鼠的细胞也是如此 在体外用IL-4刺激的细胞。因此，归纳法 磷酸化的主要生长调节底物 对IL-4的反应在STAT-6的控制下，解释了 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， 以了解IL-4通过哪些机制 确定免疫反应的生物学特征，并 确定其功能中可能适合于 激动剂拮抗剂的研究进展 为各种过敏性、自身免疫性、 传染病和炎症性疾病。

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.