Airway Epithelial NF-kB Activation by CpG DNA

细支气管上皮细胞是重要的第一道防线， 吸入的环境刺激物，包括微生物产物，如含CpG的 未甲基化的DNA本提案中要检验的假设是 CpG DNA是否诱导信号转导，最终激活 转录因子NF-κ B。提出了模式识别 Toll样受体（TLR）9由细支气管表达。 上皮细胞并启动由CpG DNA诱导的信号传导。将 检测了NF-κ B调节的多聚体的表达和活性， 免疫球蛋白受体（pIR），对伊加和IgM的转运至关重要， 支气管上皮细胞的基底面至顶面， CpG DNA最后，这些通路在细支气管中的调节 可以在治疗上利用CpG DNA对上皮细胞的作用， 通过增加分泌免疫球蛋白水平来保护。的 假设将被测试如下：具体目标1）证明， 非甲基化的免疫刺激性含CpG的DNA序列（CpG DNA）诱导 细支气管上皮细胞激活NF-κ B的信号传导事件 细胞具体目标2）证明涉及NF-κ B的信号传导事件 激活调节多聚免疫球蛋白的诱导型表达 在暴露于CpG DNA的细支气管上皮细胞中的plgr受体。具体 目的3）证明Toll样受体9（TLR 9）介导Toll样受体9的活化。 CpG DNA检测细支气管上皮细胞NF-κ B和pIgR mRNA表达 具体目的4）证明鼻内CpG DNA施用增加了 通过TLR 9介导的NF-kB在气道中分泌免疫球蛋白水平 由细支气管上皮细胞激活。

The bronchiolar epithelium is an important first line of defense against inhaled environmental stimuli, including microbial products such as CpGcontaining unmethylated DNA. The hypothesis to be tested in this proposal is whether CpG DNA induces signal transduction culminating in activation of the transcription factor NF-kappaB. It is proposed that the pattern recognition receptor (PRR) Toll Like Receptor (TLR)9 is expressed by bronchiolar epithelial cells and initiates signaling induced by CpG DNA. It will be examined whether expression and activity of the NF-kappaB-regulated polymeric immunoglobulin receptor (pIR), essential for the transport of IgA and IgM from the basal to the apical surface of bronchiolar epithelial cells, is augmented by CpG DNA. Finally, the modulation of these pathways in bronchiolar epithelium by CpG DNA may be therapeutically exploited to afford mucosal protection through the augmentation of secretary immunoglobulin levels. The hypothesis will be tested as follows: Specific aim 1) Demonstrate that unmethylated immunostimulatory CpG-containing DNA sequences (CpG DNA) induce signaling events culminating in NF-kappaB activation by bronchiolar epithelial cells. Specific aim 2) Demonstrate that signaling events involving NF-kappaB activation modulate the inducible expression of the polymeric immunoglobulin receptor (plgr) in bronchiolar epithelial cells exposed to CpG DNA. Specific aim 3) Demonstrate that Toll Like Receptor 9 (TLR9) mediates the activation of NF-kappaB and mRNA expression of pIgR in bronchiolar epithelial cells by CpG DNA. Specific aim 4) Demonstrate that intranasal CpG DNA administration augments secretary immunoglobulin levels in the airway through TLR9-mediated NF-kB activation by bronchiolar epithelial cells.