C51, IL-8 AND FMLP RECEPTOR EXPRESSION BY GLIAL CELLS

补体的来源，是疾病病理学的主要贡献者 如多发性硬化症(MS)和实验性过敏性脑脊髓炎 (EAE)，目前尚不清楚。尽管缺乏这方面的信息，但 补体在脱髓鞘疾病中的作用已被广泛研究。这些 研究表明：1)补体末端成分的存在 形成溶膜攻击复合体，2)激活补体 由髓鞘和髓鞘碱性蛋白和3)的破坏性作用 补体活化，特别是炎症、脱髓鞘和组织 毁灭。我们的初步数据显示星形胶质瘤和 原代大鼠星形胶质细胞合成补体的几种成分 该合成可被细胞因子显著上调， 干扰素-γ(干扰素-γ)。补体合成的调节 与已知的所有其他类型的细胞一样，干扰素-γ尤其令人感兴趣 合成补体对这种细胞因子的作用很难起作用。我们 假设局部补体的产生，通过星形胶质细胞的 干扰素-γ等细胞因子参与急性髓细胞白血病的发病机制 神经自身免疫性疾病，如MS或EAE。 因为补体介导的组织破坏和 神经自身免疫性疾病中的炎症，我们觉得更重要的是 充分了解星形胶质细胞补体的产生和调节。 我们将重点介绍激活替代方案所涉及的组件 补体途径(C3，因子B和D)，因为所有这些成分都是 由星形胶质瘤细胞和大鼠原代星形胶质细胞合成，并在 补体系统中的调节分子加速衰退 因素。我们将描述这些化合物的生物合成和功能。 由星形胶质瘤细胞系D54-MG产生的成分，我们有 发现是一种具有代表性的细胞类型，关于合成 互补性。我们还将研究干扰素对补体基因的诱导作用。 通过分析转录速率，稳定状态的mRNA水平， 信使核糖核酸稳定性和蛋白表达。此外，我们将划定 组织特异性顺式和反式转录调控结构 C3基因在星形胶质瘤和大鼠脑内表达的调控 原代星形胶质细胞。 本申请中提出的研究将有助于理解 补体在中枢神经系统中所起的作用。此外, 这些信息将构成比较生产和生产的基础 这些细胞类型对其他补体的调节，以及在特定的 神经疾病状态，如多发性硬化症和EAE。

The source of complement, a major contributor to the pathology of diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), is unclear. Despite this lack of information, the role of complement in demyelinating disease has been extensively studied. These studies have shown 1) the presence of the terminal components of complement which form the lytic membrane attack complex, 2) activation of complement by myelin and myelin basic protein and 3) the destructive effects of complement activation specifically inflammation, demyelination and tissue destruction. Our preliminary data demonstrate that astrogliomas and primary rat astrocytes synthesize several components of the complement system and that synthesis can be markedly upregulated by the cytokine, interferon-gamma (IFN-gamma). The regulation of complement synthesis by IFN-gamma is of particular interest as all other cell types known to synthesize complement are refractory to the effect of this cytokine. We hypothesize that local complement production, enhanced in astrocytes by the effects of cytokines such as IFN-gamma, participates in the pathogenesis of neural autoimmune diseases such as MS or EAE. Because of the potential for complement-mediated tissue destruction and inflammation in neural autoimmune diseases, we feel it is important to more fully understand the production and regulation of complement by astrocytes. We will focus on components involved in the activation of the alternative pathway of complement (C3, factors B and D) as all of these components are synthesized by astroglioma cells and rat primary astrocytes, and on one of the regulatory molecules in the complement system, decay accelerating factor. We will characterize the biosynthesis and functionality of these components as produced by the astroglioma cell line D54-MG, which we have found to be a representative cell type with respect to synthesis of complement. We will also examine the induction of complement genes by IFN- gamma by the analysis of transcription rates, steady-state mRNA levels, mRNA stability and protein expression. Further, we will delineate the tissue-specific cis and trans-acting transcriptional control structures involved in regulation of C3 gene expression in astrogliomas and rat primary astrocytes. The studies proposed in this application will contribute to understanding the role played by complement in the central nervous system. In addition, this information will form the basis for comparing the production and regulation of other complement by these cell types, as well as in specific neural disease states such as MS and EAE.