REGULATION OF IL-6 GENE EXPRESSION IN ASTROCYTES

星形胶质细胞中 IL-6 基因表达的调控

• 批准号: 3760971
• 负责人: ETTY N BENVENISTE
• 金额: --
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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/3760971
• 关键词: DNA binding protein; DNA footprinting; astrocytes; biological signal transduction; cyclic AMP; gel mobility shift assay; gene expression; genetic regulation; genetic regulatory element; genetic transcription; interferon gamma; interleukin 1; interleukin 6; laboratory rat; messenger RNA; myelinopathy; northern blottings; polymerase chain reaction; protein kinase C; second messengers; transcription factor; transfection; tumor necrosis factor alpha

The astrocyte, the major glial cell of the central nervous system (CNS), performs a wide variety of critical functions in the CNS. They include: 1) contributing to the structural integrity of the blood-brain barrier (BBB), 2) responding to CNS infection or trauma, and 3) performing as an immunocompetent cell within the CNS. In particular, the astrocyte can respond to and/or secrete a variety of cytokines. We have shown that astrocytes secrete interleukin-6 (IL-6) in response to the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interferon- gamma (IFN-gamma). These cytokines induce IL-6 production by acting both independently and synergistically. IL-6 is a pleiotropic cytokine involved in both inflammatory and immunological responses. We propose that cytokine-induced astrocyte IL-6 production is involved in mediating heightened immunological and inflammatory reactions associated with neurologic diseases such as multiple sclerosis (MS), AIDS dementia complex and experimental allergic encephalomyelitis (EAE). The multiple effects of IL-6 on various cell populations in the CNS, including autocrine stimulation of astrocytes, suggests that IL-6 has a central role in augmenting infiltration of inflammatory cells, gliosis, and intracerebral humoral immune responses, all pathogenic mechanisms involved in immune- mediated CNS disorders. As such, it is critical to first understand the basic biological mechanisms underlying induction and regulation of astrocyte IL-6 production. We will examine in detail the induction of IL-6 genes by TNF-alpha and IL-1Beta by analysis of transcription rates, steady-state mRNA levels, mRNA stability, and IL-6 protein expression. We will also investigate the intracellular mechanisms of action of TNF-alpha and IL-1Beta by examining the role of protein kinase C (PKC) and cyclic AMP (cAMP) second messenger systems in astrocyte IL-6 expression. The molecular mechanisms underlying IL-6 gene expression by astrocytes in response to TNF-alpha and IL-1Beta will be studied by examining the IL-6 DNA regulatory elements and nuclear factors utilized by cytokine-stimulated astrocytes. The two cytokines, TNF-alpha and IL-1Beta, may play a pivotal role in the induction of IL-6 production by astrocytes. The studies described in this proposal will contribute to understanding the basic cellular and molecular responses of the astrocyte to TNF-alpha and IL-1Beta. Local CNS production of IL-6 by resident astroglial cells in response to these cytokines may contribute to the pathogenesis of inflammatory demyelinating diseases, particularly with regard to B-cell differentiation and immunoglobulin secretion within the CNS.

星形胶质细胞是中枢神经系统（CNS）的主要神经胶质细胞， 在中枢神经系统中执行各种各样的关键功能。 它们包括：（1） 有助于血脑屏障（BBB）的结构完整性， 2)对中枢神经系统感染或创伤作出反应，以及3）作为 CNS内的免疫活性细胞。 特别是星形胶质细胞 应答和/或分泌多种细胞因子。 我们已经证明 星形胶质细胞分泌白细胞介素-6（IL-6）以响应细胞因子肿瘤 坏死因子-α（TNF-α）、白细胞介素-1（IL-1）和干扰素- γ（IFN-γ）。 这些细胞因子通过同时作用于细胞因子和细胞因子来诱导IL-6的产生。 独立地和协同地。 IL-6是一种多效性细胞因子， 在炎症和免疫反应中。 我们认为，苦参碱诱导的星形胶质细胞IL-6的产生参与了 介导增强的免疫和炎症反应， 患有神经系统疾病，如多发性硬化症（MS），艾滋病痴呆症 复杂性和实验性变态反应性脑脊髓炎（EAE）。 多 IL-6对CNS中各种细胞群的作用，包括自分泌 刺激星形胶质细胞，表明IL-6在 增加炎性细胞浸润、神经胶质增生和脑内 体液免疫反应，所有致病机制都涉及免疫- 介导的CNS疾病。 因此，首先了解基本的生物学机制至关重要。 星形胶质细胞IL-6产生的潜在诱导和调节。 我们将 详细检查TNF-α和IL-1 β对IL-6基因的诱导， 分析转录速率、稳态mRNA水平、mRNA稳定性 和IL-6蛋白表达。 我们还将研究细胞内 TNF-α和IL-1 β的作用机制， 蛋白激酶C（PKC）和环磷酸腺苷（cAMP）第二信使系统在 星形胶质细胞IL-6表达。 IL-6基因的分子机制 星形胶质细胞响应TNF-α和IL-1 β的表达将是 通过检测IL-6 DNA调控元件和核因子 被奎宁刺激的星形胶质细胞所利用。 两种细胞因子TNF-α和IL-1 β可能在肿瘤的发生发展中起关键作用。 星形胶质细胞诱导IL-6产生。 本文中描述的研究 该提案将有助于理解基本的细胞和分子 星形胶质细胞对TNF-α和IL-1 β的反应。 当地CNS生产 驻留的星形胶质细胞对这些细胞因子的反应中IL-6的表达可能 有助于炎性脱髓鞘疾病的发病机制， 特别是关于B细胞分化和免疫球蛋白 在CNS内分泌。