REGULATION OF IL-6 GENE EXPRESSION IN ASTROCYTES

星形胶质细胞是中枢神经系统(CNS)的主要胶质细胞， 在中枢神经系统中执行各种关键功能。它们包括：1) 有助于血脑屏障(BBB)的结构完整性， 2)应对中枢神经系统感染或创伤；3)作为 中枢神经系统内的免疫活性细胞。特别是，星形胶质细胞可以 反应和/或分泌多种细胞因子。我们已经证明了 星形胶质细胞分泌白介素6(IL-6)应答细胞因子肿瘤 肿瘤坏死因子-α、白介素1和干扰素- 伽玛(干扰素-伽马)。这些细胞因子通过两者共同作用诱导IL-6的产生 独立地和协同地。IL-6是一种多效性细胞因子 在炎症和免疫反应方面。 我们认为细胞因子诱导的星形胶质细胞IL-6的产生参与了 介导相关的高度免疫和炎症反应 患有多发性硬化症(MS)、艾滋病痴呆症等神经系统疾病 复杂性实验性变态反应性脑脊髓炎(EAE)。多面性 IL-6对中枢不同细胞群包括自分泌的影响 对星形胶质细胞的刺激，表明IL-6在 增加炎症细胞、胶质细胞和脑内的渗透 体液免疫反应，所有与免疫有关的致病机制- 介导的中枢神经系统紊乱。 因此，首先了解基本的生物学机制是至关重要的。 星形胶质细胞产生IL-6的潜在诱导和调节。我们会 详细检测TNF-α和IL-1β对IL-6基因的诱导作用 分析转录速率、稳态信使核糖核酸水平、信使核糖核酸稳定性、 IL-6蛋白表达。我们还将调查细胞内 肿瘤坏死因子-α和白介素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 星形胶质细胞IL-6的表达。IL-6基因的分子机制 星形胶质细胞对肿瘤坏死因子-α和白介素1β的反应 通过检测IL-6DNA调控元件和核因子进行研究 被细胞因子刺激的星形胶质细胞所利用。 这两种细胞因子，即肿瘤坏死因子-α和白介素1-β，可能在 星形胶质细胞诱导产生IL-6。在这篇文章中描述的研究 建议将有助于理解基本的细胞和分子 星形胶质细胞对肿瘤坏死因子-α和白介素1-β的反应本地CNS生产 常驻星形胶质细胞对这些细胞因子的IL-6的反应可能 与炎症性脱髓鞘疾病的发病机制有关， 尤其是在B细胞分化和免疫球蛋白方面 中枢神经系统内的分泌物。

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.