Airway Epithelial NF-kB Activation by CpG DNA

细支气管上皮是一条重要的第一道防线。 吸入的环境刺激，包括含有CpG的微生物产品 未甲基化的DNA。这项提议中要检验的假设是 CpG DNA是否诱导信号转导，最终激活 转录因子核因子-kappaB。有人提出，模式识别 受体(PRR)Toll样受体(TLR)9由细支气管膜表达 CpG DNA诱导的上皮细胞和启动信号转导。会是 检测核因子-kappaB调节的聚合物的表达和活性 免疫球蛋白受体(PIR)，对IgA和IgM的转运至关重要 细支气管壁上皮细胞顶面的底部增大 由CpG DNA检测。最后，这些通路在细支气管中的调节 CpG DNA介导的上皮细胞可用于治疗提供粘膜 通过提高分泌性免疫球蛋白水平进行保护。这个 假设将被检验如下：具体目标1)证明 非甲基化免疫刺激CpG DNA序列(CpG DNA)诱导 细支气管上皮最终激活核因子-kappaB的信号转导事件 细胞。特定目的2)证明涉及核因子-kappaB的信号事件 激活调节聚合免疫球蛋白的诱导性表达 CpG DNA作用于细支气管壁上皮细胞的受体(PLGR)特定的 目的3)证实Toll样受体9(TLR9)介导血管紧张素转换酶激活 CpG DNA检测细支气管壁上皮细胞核因子-kappaB和pIgR的表达。 具体目的4)证明鼻腔注射CpG DNA可增强 TLR9介导的核因子-kB对呼吸道分泌型免疫球蛋白水平的影响 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.