INTERLEUKIN 4 (IL-4)

白细胞介素 4 (IL-4)

• 批准号: 3746555
• 负责人: W E 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/3746555
• 关键词: CD antigens; T cell receptor; T lymphocyte; antigen presentation; cell differentiation; cell population study; cytokine receptors; gene induction /repression; genetically modified animals; growth factor receptors; insulin receptor; interferon gamma; interleukin 2; interleukin 4; laboratory mouse; phosphorylation; protein structure function; protein tyrosine kinase; receptor binding

Naive CD4+ T cells produce interleukin-2 (IL-2) upon stimulation by antigen and antigen-presenting cells but can be induced to differentiate into cells that principally produce interleukin-4 (IL-4) or interferon gamma (IFNgamma). The determination of which lymphokine is dominantly produced has a major impact on the protective value of the immune response. Utilizing naive CD4+ T cells from T cell receptor transgenic mice, it was shown that IL-4 itself is the principal factor determining whether T cells develop into IL-4 producers; in addition, IL-4 strikingly suppresses priming for IFNgamma production. In the absence of IL-4, priming leads to cells that produce moderate amounts of IFNgamma. Addition of IL-12 to the priming culture upregulates priming for IFNgamma production and allows such priming to occur even in the presence of IL-4. The physiologic source of IL-4 that determines this pattern of differentiation is a matter of great importance. A specialized population of splenic CD4+ T cells expressing the NK1.1 marker has been identified and shown to promptly produce IL-4 upon in vivo activation with anti-CD3 antibody or superantigens. Two strains of mice (SJL and beta2-microglobulin knockout mice) have both a deficiency in IL-4 production by these cells and impaired differentiation to the production of IL-4 and to the secretion of IgE implying that these cells have an important role in the production of IL-4 at the outset of immune responses. IL-4 action is mediated by binding to a high affinity receptor. This receptor consists of two chains. One binds IL-4 with substantial affinity and also determines the specificity of the signalling pathway. The other (the gamma chain of the IL-2 receptor or gammac) is essential for transducing biochemical signals. The binding of IL-4 to the IL-4 receptor complex results in the phosphorylation of a 170 kDa substrate, designated 4PS, an analog of insulin receptor substrate-1 (IRS-1). Phosphorylation of 4PS/IRS-1 is lost in truncation mutants of the receptor that delete the most membrane proximal tyrosine. The sequence around that tyrosine is homologous to the sequence around a comparable tyrosine in the insulin and IGF-1 receptors; this motif has been termed the I4R motif. A fusion protein containing the I4R motif binds the substrate and the kinase that can catalyze the phosphorylation of IRS-1. The I4R motif appears to act as a docking site for 4PS/IRS-1.

天真的CD4+ T细胞在刺激时产生白介素-2（IL-2） 抗原和抗原呈递细胞，但可以诱导 主要产生白介素-4（IL-4）或干扰素的细胞 伽玛（Ifngamma）。 哪种淋巴因子的确定主要是 生产对免疫的保护价值有重大影响 回复。 利用T细胞受体转基因的幼稚CD4+ T细胞 小鼠，证明IL-4本身是确定的主要因素 T细胞是否发展为IL-4生产者；另外，IL-4令人惊讶 抑制IFNGAMMA生产的启动。 在没有IL-4的情况下， 启动会导致产生适量的IFNGAMMA的细胞。 在启动培养物中添加IL-12可以上调IFNGAMMA的启动 生产并允许在IL-4存在的情况下进行这种启动。 IL-4的生理来源决定了这种模式 差异化是一个非常重要的问题。 专业 表达NK1.1标记的脾脏CD4+ T细胞的种群已经 在体内激活后识别并显示出迅速产生IL-4 抗CD3抗体或超抗原。 两种菌株（SJL和 beta2-microglobolin敲除小鼠）既缺乏IL-4 这些细胞的生产并损害了生产的分化 IL-4的分泌，这意味着这些细胞具有 免疫开始时在生产IL-4中的重要作用 回答。 IL-4作用是通过与高亲和力受体结合来介导的。 这 受体由两个链组成。 一个绑定IL-4具有实质性 亲和力，还确定信号通路的特异性。 另一个（IL-2受体或γ的伽马链）是必不可少的 用于转导生化信号。 IL-4与IL-4的结合 受体复合物导致170 kDa底物的磷酸化， 指定的4PS，一种胰岛素受体底物-1（IRS-1）的类似物。 4PS/IRS-1的磷酸化在截短突变体中丢失 删除最近端酪氨酸的受体。 序列 酪氨酸周围与可比的序列同源 胰岛素和IGF-1受体中的酪氨酸；这个主题被称为 I4R主题。 包含I4R基序的融合蛋白结合 可以催化IRS-1的磷酸化的底物和激酶。 I4R图案似乎是4PS/IRS-1的对接站点。