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首页> 外文学位 >Activation of host cell gene expression by respiratory syncytial virus infection of the alveolar epithelial cell line A549: A role for the redox responsive transcription factor NF-kappaB.
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Activation of host cell gene expression by respiratory syncytial virus infection of the alveolar epithelial cell line A549: A role for the redox responsive transcription factor NF-kappaB.

机译：呼吸道合胞病毒感染肺泡上皮细胞系A549激活宿主细胞基因表达：氧化还原反应性转录因子NF-κB的作用。

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摘要

Respiratory syncytial virus (RSV) is a major cause of infectious bronchiolitis and is responsible for significant morbidity and mortality. While those at highest risk of infection include infants, the elderly and immunocompromised adults, no one generates long-term, protective immunity to RSV. Links have been established between severe RSV infection in infancy and subsequent development of asthma and between RSV disease and exacerbation of asthma in all age groups.;Chemokines and cytokines are induced by RSV from infected respiratory epithelia. Using the alveolar epithelial cell line A549 as a model, we have shown that RSV infection leads to the induction of protein and mRNA expression of the chemokines interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, and regulated upon activation, normal T cell expressed and secreted (RANTES) as well as the cytokine IL-15. The primary objectives of this work were to identify genes activated in A549 cells by RSV and investigate the mechanism of their induction. Ribonuclease protection assay (RPA) showed increased levels of a variety of mRNA including IL-1alpha, IL-6, IL-8, IL-15, lymphotoxin (LT)-beta, MCP-1 and RANTES. Similar mRNA profiles were induced by the proinflammatory cytokine, tumor necrosis factor (TNF) alpha. However, the kinetics of induction by the cytokine were different from those of RSV, which were lower in magnitude and delayed. Addition of two inhibitors, dexamethasone (DEX), a synthetic glucocorticoid, and N-acetyl-L-cysteine (NAC), an antioxidant precursor to glutathione, demonstrated discriminating effects on gene induction. NAC consistently inhibited RSV inductions of mRNAs while not inhibiting or even enhancing TNFalpha induction. In contrast, DEX inhibited predominantly TNFalpha induction.;Analysis of transcription factor binding activity showed that both agonists enhanced NF-kappaB translocation with RSV preferentially augmenting RelA. NAC and DEX did not decrease binding of RelA or NF-kappaB1 induced by TNFalpha. Inhibition of RSV induced binding of RelA was predominant over NF-kappaB1 by both DEX and NAC. While the mechanisms of induction of genes by RSV and TNFalpha each utilize enhancement of NF-kappaB binding, the proteins involved in the complexes differ indicating that different mechanisms are used by the agonists. These mechanisms lead to specific induction of chemokines and cytokines by RSV in contrast with TNFalpha.
机译：呼吸道合胞病毒（RSV）是传染性毛细支气管炎的主要原因，并导致大量发病和死亡。虽然感染风险最高的人群包括婴儿，老年人和免疫功能低下的成年人，但没有人对RSV产生长期的保护性免疫。在所有年龄段的婴儿中，严重的RSV感染与随后的哮喘发展之间以及在所有年龄段的RSV疾病与哮喘恶化之间都建立了联系。感染呼吸道上皮细胞的RSV诱导趋化因子和细胞因子。使用肺泡上皮细胞系A549作为模型，我们已显示RSV感染可诱导趋化因子白介素（IL）-8，单核细胞趋化蛋白（MCP）-1和活化后的蛋白和mRNA表达的诱导，正常的T细胞表达和分泌（RANTES）以及细胞因子IL-15。这项工作的主要目的是鉴定RSV在A549细胞中激活的基因，并研究其诱导机制。核糖核酸酶保护试验（RPA）显示各种mRNA的水平升高，包括IL-1α，IL-6，IL-8，IL-15，淋巴毒素（LT）-β，MCP-1和RANTES。促炎细胞因子，肿瘤坏死因子（TNF）α诱导了类似的mRNA分布。然而，细胞因子的诱导动力学不同于RSV，其幅度较低且延迟。两种抑制剂，地塞米松（DEX）（一种合成的糖皮质激素）和N-乙酰-L-半胱氨酸（NAC）（一种谷胱甘肽的抗氧化剂前体）的添加，对基因诱导具有区分作用。 NAC始终抑制mRNA的RSV诱导，而不抑制甚至不增强TNFalpha诱导。相反，DEX主要抑制TNFα的诱导。转录因子结合活性的分析表明，两种激动剂均通过RSV优先增强RelA来增强NF-κB易位。 NAC和DEX不会降低TNFalpha诱导的RelA或NF-κB1的结合。 DEX和NAC对RSV诱导的RelA结合的抑制作用主要超过NF-kappaB1。尽管RSV和TNFalpha诱导基因的机制都利用了NF-κB结合的增强，但复合物中所涉及的蛋白质却有所不同，表明激动剂使用了不同的机制。与TNFα相反，这些机制导致RSV特异性诱导趋化因子和细胞因子。

著录项

  • 作者

    Carpenter, Laura Rosenbalm.;

  • 作者单位

    Rush University.;

  • 授予单位 Rush University.;
  • 学科 Biology Microbiology.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 115 p.
  • 总页数 115
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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