INTERLEUKIN 4 SIGNALLING IN ASTROCYTES

星形胶质细胞中的白细胞介素 4 信号传导

• 批准号: 2272984
• 负责人: BARBARA P BARNA
• 金额: $ 18.85万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2272984
• 关键词: astrocytes; astrocytoma; cyclins; cytokine receptors; epidermal growth factor; gene induction /repression; glioblastoma multiforme; human subject; immunoprecipitation; interleukin 4; mitogens; neurogenesis; neuropharmacology; polymerase chain reaction; protein kinase; receptor binding; receptor expression; tissue /cell culture; transfection; western blottings

Intercellular communication within the neural and immune systems frequently involves cell type-specific responses to common signalling proteins such as cytokines. The cytokine, Interleukin 4 (IL-4), can be produced by T lymphocytes and by non-T cells within the central nervous system (CNS). Unlike many cytokines that stimulate astrocyte growth, our data indicate that IL-4 inhibits DNA synthesis and proliferation in human, non-neoplastic astrocytes derived from adult cortex. Cell lines derived from low grade astrocytic tumors (astrocytomas) are also inhibited by IL- 4, but lines from highly malignant astrocytomas (glioblastoma multiforme) are refractory to IL-4 despite expression of IL-4 receptors. Based upon our findings we hypothesize that IL-4 represents an anti-mitogenic, differentiating signal in normal astrocytes - a property which is lost in malignant astrocytes. The overall goal of this proposal is to characterize mechanisms of IL-4-mediated growth regulation in human astrocytes, utilizing as a model system, IL-4 responsive and non- responsive human astrocytic cell lines derived, respectively, from low grade astrocytoma and glioblastoma multiforme. Specific Aims are to: (1) Determine the relationship of IL-4 receptor expression to proliferation in astrocytes. (Are IL-4 receptors modified by mitogenic {EGF} or non-mitogenic {IL-4} signals? Conversely, does IL-4 modify heterologous receptors for mitogenic {EGF} ligands?) (2) Identify mechanisms of IL-4-mediated inhibition of DNA synthesis and proliferation. (Are cell cycle components such as G1/S phase cyclins {Cyclins E and D1} and/or associated cyclin-dependent protein kinases, {cdk2 and cdk4} affected by IL-4? (3) Ascertain the physiological relevance of IL-4 receptor expression to astrocyte proliferation in vivo. (Are IL-4 receptors differentially expressed {by RT-PCR analysis} in tissues characterized by reactive vs. quiescent non-neoplastic astrocytes, or low grade astrocytoma vs glioblastoma multiforme?) Elucidation of processes involved in governing normal adult human astrocyte proliferation could potentially highlight new areas for therapeutic intervention in neoplastic or non-neoplastic diseases of the CNS.

神经和免疫系统内的细胞间通信 经常涉及对常见信号的特定于细胞类型的响应 蛋白质，例如细胞因子。 细胞因子，白介素4（IL-4）可以是 由T淋巴细胞和中枢神经内的非T细胞产生 系统（CNS）。 与许多刺激星形胶质细胞生长的细胞因子不同，我们 数据表明IL-4抑制人类的DNA合成和增殖， 源自成人皮质的非肿瘤星形胶质细胞。 细胞系得出 从低年级的星形胶质细胞肿瘤（星形胶质细胞瘤）也受到IL-的抑制 4，但是来自高度恶性星形胶质细胞瘤（多形胶质母细胞瘤）的线 尽管表达了IL-4受体，但对IL-4的难治性。 基于 我们的发现我们假设IL-4代表一种抗裂纹， 在正常星形胶质细胞中区分信号 - 丢失的特性 恶性星形胶质细胞。 该提议的总体目标是 表征人类IL-4介导的生长调节的机制 星形胶质细胞用作模型系统，IL-4响应且非 - 反应敏感的人星形细胞细胞系分别从低低 级星形细胞瘤和胶质母细胞瘤多形。 具体目的是： （1）确定IL-4受体表达与 星形胶质细胞增殖。 （是通过有丝分裂修饰的IL-4受体 {egf}或非裂纹{IL-4}信号？ 相反，IL-4修改 有丝分裂的异源受体{EGF}配体？） （2）确定IL-4介导的DNA合成抑制和 增殖。 （是细胞周期成分，例如G1/s相细胞周期蛋白 {细胞周期蛋白E和D1}和/或相关的细胞周期蛋白依赖性蛋白激酶， {CDK2和CDK4}受IL-4影响？ （3）确定IL-4受体表达与 体内星形胶质细胞增殖。 （是IL-4受体差异的 以反应性V为特征的组织中表示{通过RT-PCR分析}。 静止的非肿瘤星形胶质细胞或低级星形胶质细胞瘤与 胶质母细胞瘤多形？） 阐明涉及正常成人人类的过程 星形胶质细胞增殖可能会突出显示的新领域 对肿瘤或非肿瘤疾病的治疗干预 CNS。