• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Modulation of TNF-alpha-mediated acute lung inflammation: A role for IL-1beta and soluble TNF receptors.
【24h】

Modulation of TNF-alpha-mediated acute lung inflammation: A role for IL-1beta and soluble TNF receptors.

机译：TNF-α介导的急性肺炎症的调节：IL-1beta和可溶性TNF受体的作用。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are key mediators of numerous lung inflammatory diseases. Induced by similar stimuli, in many cell types IL-1beta modifies expression and solubilization of the two TNF receptors, TNFR1 and TNFR2. These proteins are cleaved from the cell surface primarily by the metalloprotease TNF-alpha converting enzyme (TACE) generating soluble forms still capable of binding TNF-alpha. Investigators postulate that the shed receptors either act as natural antagonists or as a TNF-alpha reservoir extending the half-life of the cognate ligand. Based on these observations, IL-1beta effects on lung TNF-alpha-mediated inflammatory responses, as well as on TNF receptor expression and shedding, both in vitro and in vivo were investigated. Finally, the roles of the two soluble TNF receptors (sTNFR) on altering ligand-induced inflammation and cytotoxicity were analyzed. Studies utilizing an in vitro culture system, murine epithelial type II-like cells (MLE-15), and transgenic IL-1beta null mice showed that the interleukin enhances acute, TNF-alpha-mediated pulmonary inflammatory processes. In vitro, IL-1beta induced MLE-15 surface TNF receptor expression which correlated with increased mRNA levels and protein secretion of the two neutrophil chemoattractants macrophage inflammatory protein (MIP-2) and KC following TNF-alpha exposure. Further studies investigating the regulation of the two receptors demonstrated a counter-regulatory role for each; TNFR1 expression was necessary for interleukin-mediated TNFR2 shedding and surface expression and vice a versa. In vivo studies corroborated these findings. IL-1f3 KO mice instilled with TNF-alpha had decreased neutrophil influx measured in the lavage fluid of the lung. This correlated with a decrease in lavage sTNFR1 and MIP-2, although sTNFR2 and KC were unaffected. Finally, at a ratio of approximately 1:1 to 1:25, sTNFR1:sTNFR2 functioned as TNF-alpha antagonists in vitro . Taken together, the studies in this thesis suggest that IL-1beta modulates TNF-alpha-mediated inflammatory lung diseases by altering TNF receptor shedding and expression in epithelial cells, resulting in altered chemoattractant production in response to TNF-alpha, hence augmenting recruitment of inflammatory cells.
机译：肿瘤坏死因子-α（TNF-alpha）和白介素-1beta（IL-1beta）是许多肺炎性疾病的关键介质。由相似的刺激诱导，在许多细胞类型中，IL-1beta会修饰两种TNF受体TNFR1和TNFR2的表达和增溶。这些蛋白质主要是通过金属蛋白酶TNF-α转换酶（TACE）从细胞表面切割的，产生的可溶性形式仍然能够结合TNF-α。研究人员推测，脱落的受体要么充当天然拮抗剂，要么充当TNF-α贮库，延长同源配体的半衰期。基于这些观察，研究了IL-1β在体外和体内对肺TNF-α介导的炎症反应以及TNF受体表达和脱落的影响。最后，分析了两种可溶性TNF受体（sTNFR）在改变配体诱导的炎症和细胞毒性中的作用。利用体外培养系统，鼠类上皮II型细胞（MLE-15）和转基因IL-1beta无效小鼠进行的研究表明，白介素增强了急性的，TNF-α介导的肺部炎症过程。在体外，IL-1β诱导了MLE-15表面TNF受体的表达，这与两种中性粒细胞趋化性巨噬细胞炎性蛋白（MIP-2）和KC在TNF-α暴露后的mRNA水平升高和蛋白分泌相关。进一步研究两种受体的调节作用表明，每种受体都有相反的调节作用。 TNFR1表达对于白介素介导的TNFR2脱落和表面表达是必需的，反之亦然。体内研究证实了这些发现。滴注TNF-α的IL-1f3 KO小鼠在肺灌洗液中的嗜中性粒细胞流入减少。尽管sTNFR2和KC不受影响，但这与灌洗液sTNFR1和MIP-2的减少有关。最后，sTNFR1：sTNFR2以约1：1至1:25的比例在体外起TNF-α拮抗剂的作用。综上所述，本论文的研究表明，IL-1β通过改变上皮细胞中TNF受体的脱落和表达来调节TNF-α介导的炎性肺疾病，从而导致对TNF-α的化学引诱剂产生改变，从而增加了炎症的募集。细胞。

著录项

  • 作者

    Saperstein, Sara C.;

  • 作者单位

    University of Rochester.;

  • 授予单位 University of Rochester.;
  • 学科 Health Sciences Toxicology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 211 p.
  • 总页数 211
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学（毒理学）;
  • 关键词

  • 入库时间 2022-08-17 11:38:28

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号