INTERLEUKINS AND THEIR RECEPTORS IN TUMOR BIOLOGY AND AIDS

肿瘤生物学和艾滋病中的白细胞介素及其受体

• 批准号: 2568987
• 负责人: R PURI
• 金额: --
• 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/2568987
• 关键词: AIDS; Primates; antineoplastics; athymic mouse; binding proteins; biological signal transduction; brain; cell type; crosslink; cytokine receptors; cytotoxicity; dosage; drug quality /standard; drug screening /evaluation; exotoxins; human tissue; interleukin 13; interleukin 4; laboratory rat; necrosis; neoplastic cell; neoplastic growth; pharmacokinetics; phosphorylation; receptor expression; transcription factor

IL-4 is a pleiotropic immune regulatory cytokine and is being tested in the clinic for the treatment of a variety of human cancers. The soluble form of IL-4 receptor (IL-4R) is being used for the treatment of bronchial asthma. Since we have discovered that a variety of solid human cancer cells express IL-4R, studies are being undertaken to characterize structure, function, signal transduction and targeting of IL-4R expressed on immune cells and cancer cells. IL-4R directed targeting of a Pseudomonas exotoxin (PE), and regulation and interaction of IL-4R with other cytokines, cytokine receptors and regulatory proteins such as HIV-1 tat is also being investigated. These ongoing studies will reveal the mechanism of IL-4 action and IL-4 induced toxicity. A. Structure and function of IL-4R on tumor cells. Crosslinking studies have demonstrated that IL-4R on human cancer cells are composed of two major proteins of 140 kDa and 70 kDa. Immune cells also expressed two to three IL-4 binding proteins of 140 kDa, 70 kDa and 64 kDa depending on cell types examined. It has been shown that IL-2R gamma chain is associated with IL-4R and is a necessary component for IL-4 signalling. The 64 kDa protein appears to be gamma chain, however, the identity of the 70 kDa protein is not clear. Immunoprecipitation studies demonstrated that gamma is not a component of IL-4R in solid cancer cells. We have demonstrated that solid cancer cells express large numbers of IL-13R. Since IL-13 competed for the binding sites of IL-4 and the size of IL-13R binding protein is similar to that of IL-4R 70 kDa protein we proposed that IL-13R is a component of IL-4R. B. IL-4R directed targeting of a Pseudomonas exotoxin. The IL-4R expressed on human tumor cells were targeted with a chimeric protein comprised of IL-4 and PE. Newer generations of IL4-PE toxins have improved binding. In addition, this chimeric protein was more cytotoxic to IL-4R positive tumor cells. Anti-tumor studies were carried out in nude mice using new toxin in xenograft model bearing human epidermoid carcinoma. Circularly permuted IL4-toxin can cause durable complete responses in mice. Pre-clinical studies are underway to explore optimal route and schedule of therapy and type of human tumor which will be most susceptible. Since many chimeric proteins composed of cytokines, antibody and PE are being used in the clinic these studies will provide insight into the mechanism of action and toxicity. C. IL-4 induced signal Transduction: IL-4 has been shown to induce phosphorylation of insulin response substrate (IRS-1), IL-4R and Janus kinases (JAK) 1, and 3. The gamma chain of IL-4R has been shown to be required for the phosphorylation of IRS-1 and JAK3 in IL-4 signalling pathway. Our studies show that in the absence of gamma chain, IL-4 can induce phosphorylation of IRS-1 and JAK3 is not involved in IL-4R signalling pathway in tumor cells. Studies are ongoing to identify IL-4R signalling differences between immune cells and cancer cells.

IL-4是一种多效性免疫调节细胞因子， 治疗多种人类癌症的诊所。可溶性 IL-4受体（IL-4 R）的一种形式被用于治疗 支气管哮喘 自从我们发现各种各样的固体人类 癌细胞表达IL-4 R，正在进行研究以表征 表达IL-4 R的结构、功能、信号转导和靶向性 对免疫细胞和癌细胞的影响。IL-4 R定向靶向a 假单胞菌外毒素（PE），以及IL-4 R与 其它细胞因子、细胞因子受体和调节蛋白如HIV-1 警方亦正调查达特。这些正在进行的研究将揭示 IL-4的作用机制和IL-4诱导的毒性。 A.结构和 IL-4 R对肿瘤细胞的作用。交联研究表明， 人类癌细胞上的IL-4 R由两种主要蛋白质组成， 140 kDa和70 kDa。免疫细胞也表达两到三种IL-4结合 140 kDa、70 kDa和64 kDa的蛋白质，这取决于检查的细胞类型。 已经表明IL-2 R γ链与IL-4 R相关， IL-4信号传导的必要成分。64 kDa蛋白似乎 然而，70 kDa蛋白的身份尚不清楚。 免疫沉淀研究表明，伽马不是一种成分， IL-4 R在实体癌细胞中的表达。我们已经证明了实体癌 细胞表达大量的IL-13 R。自从IL-13竞争 IL-4的结合位点和IL-13 R结合蛋白的大小相似 对于IL-4 R 70 kDa蛋白，我们提出IL-13 R是一个成分， IL-4R B。IL-4 R指导的假单胞菌外毒素的靶向。的 在人肿瘤细胞上表达的IL-4 R被嵌合的 蛋白质由IL-4和PE组成。新一代的IL 4-PE毒素 改进绑定。此外，这种嵌合蛋白具有更强的细胞毒性， IL-4 R阳性肿瘤细胞。 抗肿瘤研究在 新毒素在荷人表皮样瘤裸鼠移植瘤模型中的应用 carcinoma. 循环排列的IL 4毒素可导致持久的完全性 小鼠的反应。临床前研究正在进行中，以探索最佳的 治疗的途径和时间表以及将是最常见的人类肿瘤的类型 易受影响 由于许多嵌合蛋白由细胞因子组成， 这些研究将提供抗体和PE用于临床 深入了解作用机制和毒性。 C. IL-4诱导 信号转导：IL-4已显示诱导 胰岛素应答底物（IRS-1）、IL-4 R和Janus激酶（JAK）1，以及 3. IL-4 R的γ链已被证明是免疫调节所必需的。 IL-4信号通路中IRS-1和JAK 3的磷酸化。我们的研究 显示在γ链不存在时，IL-4可诱导磷酸化 IRS-1和JAK 3的结合不参与肿瘤中IL-4 R信号通路 细胞正在进行研究以确定IL-4 R信号传导差异 免疫细胞和癌细胞之间的联系