INTERLEUKIN-4 AND THEIR RECEPTORS IN TUMOR BIOLOGY AND AIDS

IL-4是一种多效性免疫调节细胞因子，目前正在进行测试 治疗多种人类癌症的诊所。可溶的 白介素4受体(IL-4R)的形式正被用于治疗 支气管哮喘。自从我们发现了各种各样的固体人类 癌细胞表达IL-4R，正在进行研究以确定其特征 IL-4R的结构、功能、信号转导和靶向 免疫细胞和癌细胞。IL-4R定向靶向 假单胞菌外毒素(PE)及其与IL-4R的调节和相互作用 其他细胞因子、细胞因子受体和调节蛋白，如HIV-1 TAT也在接受调查。这些正在进行的研究将揭示 IL-4的作用机制及IL-4的毒性A.结构和 IL-4R在肿瘤细胞中的作用交联性研究表明 人癌细胞上的IL-4R主要由两种蛋白质组成 140 kDa和70 kDa。免疫细胞也表达两到三个IL-4结合 140 kDa、70 kDa和kDa的蛋白质，取决于所研究的细胞类型。 已有研究表明，IL-2R-γ链与IL-4R相关，是 这是IL-4信号传递的必要组成部分。KDa蛋白似乎 然而，70 kDa的蛋白是伽玛链，其身份尚不清楚。 免疫沉淀研究表明，伽马不是 IL-4R在实体癌细胞中的表达。我们已经证明了实体癌 细胞大量表达IL-13R。由于IL-13竞争 IL-4的结合部位和IL-13R结合蛋白的大小相似 对于IL-4R 70 kDa蛋白，我们认为IL-13R是 IL-4R的表达。B.IL-4R定向靶向一种假单胞菌外毒素。这个 表达在人肿瘤细胞上的IL-4R被嵌合体靶向 由IL-4和PE组成的蛋白质。新一代的IL4-PE毒素 改进了绑定。此外，这种嵌合蛋白具有更强的细胞毒性。 IL-4R阳性的肿瘤细胞。抗肿瘤研究在#年进行。 裸鼠移植人表皮样瘤模型中使用新型毒素的研究 癌症。循环排列的IL4-毒素可以导致持久的完全性 小鼠的反应。临床前研究正在进行中，以探索最佳 治疗的路线和时间表以及最常见的人类肿瘤类型 易受影响。由于许多嵌合蛋白由细胞因子组成， 抗体和PE正在临床上使用这些研究将提供 深入了解其作用机制和毒性。C.诱导的IL-4 信号转导：IL-4诱导细胞外信号转导通路的磷酸化 胰岛素反应底物(IRS-1)、IL-4R和Janus激酶(JAK)1，以及 3.IL-4R的伽马链已被证明是 IRS-1和JAK3在IL-4信号通路中的磷酸化我们的研究 表明在没有伽马链的情况下，IL-4可以诱导磷酸化 IRS-1和JAK3在肿瘤中不参与IL-4R信号通路 细胞。识别IL-4R信号差异的研究正在进行中 免疫细胞和癌细胞之间的关系。

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.