INTERLEUKIN-4 AND THEIR RECEPTORS IN TUMOR BIOLOGY AND AIDS

肿瘤生物学和艾滋病中的 INTERLEUKIN-4 及其受体

• 批准号: 3770375
• 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/3770375
• 关键词: AIDS; Burkitt's lymphoma; Pseudomonas; chimeric proteins; crosslink; cytokine; cytokine receptors; endotoxins; exotoxins; fibroblasts; gene induction /repression; histocompatibility antigens; human tissue; interleukin 4; lymphocyte; neoplasm /cancer pharmacology; neoplastic cell; protein structure function; regulatory gene; renal cell carcinoma; tissue /cell culture; vascular endothelium

We have discovered that a variety of human solid tumor cells express Interleukin-4 Receptors (IL-4R). In addition, IL-4R are upregulated by HIV regulatory gene tat on human Burkitt's lymphoma (Raji) cell line. Studies were carried out to characterize: A. the functional significance and structure of IL-4R on human solid and hematologic tumors; B. IL-4R directed targeting of a Pseudomonas endotoxin (PE); C. Mechanism of IL-4R regulation by HIV-tat gene. A. Structure and Function of IL-4 receptors on tumor cells. IL-4 caused the inhibition of tumor cell growth in tissue culture and this inhibition was of different degrees in different human tumors. In contrast, IL-4 caused modest stimulation of growth in normal human endothelial and fibroblast cell lines. Human renal cell carcinoma (RCC) cells were most susceptible to the growth inhibitory effects of IL-4. Experiments are in progress to determine other functions of IL-4R (e.g. regulation of HLA antigens, IL-4R, and cytokine production) on these tumor cells. In preliminary experiments, IL-4R structure and properties appear to be similar in both RCC and human B cell derived lymphoma cell line. In both cell types IL-4R appear to be internalized and recycled. Structure of IL- 4R and possibility of association of other subunit(s) to IL-4R is being explored by cross linking and immunoprecipitation experiments using anti- IL-4R antibodies. 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. This protein was highly cytotoxic to IL-4R positive tumor cells, however, normal cells e.g. peripheral blood lymphocytes, endothelial cells and fibroblasts were somewhat resistant to the cytotoxic effect of IL4-PE. Studies are underway to examine anti- tumor properties of this chimeric protein against a variety of human cancers.

我们已经发现多种人类实体瘤细胞表达 白细胞介素-4受体（IL-4 R）。 此外，IL-4 R被上调， HIV调节基因tat在人伯基特淋巴瘤（Raji）细胞系上的作用 进行了研究以表征：A.的功能意义 和IL-4 R在人实体瘤和血液肿瘤上的结构; B. IL-4R 定向靶向假单胞菌内毒素（PE）; C. IL-4 R的作用机制 HIV-tat基因的调控。 A.肿瘤细胞上IL-4受体的结构和功能 IL-4引起 在组织培养中抑制肿瘤细胞生长和这种抑制 在不同的人类肿瘤中有不同的程度。 相反，IL-4 引起正常人内皮细胞生长的适度刺激， 成纤维细胞系。 人肾细胞癌（RCC）细胞中， 对IL-4的生长抑制作用敏感。 实验正在 确定IL-4 R的其他功能（例如HLA的调节）的进展 抗原、IL-4 R和细胞因子产生）。 在 初步实验，IL-4 R的结构和性质似乎是 在RCC和人B细胞衍生淋巴瘤细胞系中类似。 无论是 细胞类型IL-4 R似乎被内化和再循环。 IL-的结构 IL-4 R和其他亚基与IL-4 R相关的可能性正在研究中。 通过交联和免疫沉淀实验，使用抗- IL-4 R抗体。 B。IL-4 R指导的假单胞菌外毒素的靶向。 述IL-4 r 用嵌合蛋白靶向人肿瘤细胞上表达的 由IL-4和PE组成。 该蛋白对IL-4 R具有很强的细胞毒性 阳性肿瘤细胞，然而，正常细胞，例如外周血 淋巴细胞、内皮细胞和成纤维细胞对 IL 4-PE的细胞毒作用。 目前正在进行研究， 这种嵌合蛋白对多种人的肿瘤特性 癌的