Interaction with CREB binding protein modulates the activities of Nrf2 and NF-κB in cystic fibrosis airway epithelial cells
Interaction with CREB binding protein modulates the activities of Nrf2 and NF-κB in cystic fibrosis airway epithelial cells
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DOI：
10.1152/ajplung.00156.2011
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发表时间：
2012-06-01
影响因子：
4.9
通讯作者：
Kelley, Thomas J.
中科院分区：
文献类型：
--
作者：
Ziady, Assem G.;Sokolow, Andrew;Kelley, Thomas J.
齐亚迪AG， Sokolow A, Shank S, Corey D, Myers R, Plafker S, Kelley TJ。与CREB结合蛋白的相互作用调节囊性纤维化气道上皮细胞中Nrf2和NF-kappa B的活性。[J] .中国生物医学工程学报，2016,31(2):555 - 557。首次发表于2012年3月30日；doi: 10.1152 / ajplung.00156.2011。-囊性纤维化（CF）以炎性肺部疾病为特征，可显著增加发病率和死亡率。气道上皮细胞在CF的炎症信号传导中发挥作用，并在调节炎症的信号级联反应中表现出许多功能障碍。之前，我们报道了核因子红细胞衍生样2 （Nrf2）的活性，一种调节抗氧化和细胞保护蛋白表达的转录因子，在CF上皮中降低(7)。在本报告中，我们在体外研究了人气道上皮细胞系和原代细胞以及Delta F508 CF突变小鼠鼻上皮中Nrf2失调的机制。我们发现，与非CF细胞相比，camp介导的信号传导显著降低了CF细胞中Nrf2的活性。cAMP的竞争对手Rp-cAMPS主要通过增加转录因子的核积累来显著纠正CF细胞中Nrf2的活性。此外，我们发现rp - camp显著降低CF细胞炎症刺激后NF-kappa B的激活。进一步的研究表明，Nrf2和NF-kappa B竞争转录辅激活因子cAMP响应元件结合蛋白（CREB）结合蛋白（CBP）， Rp-cAMPS将CBP关联转向Nrf2。因此，我们的研究结果提供了对CF跨膜调节功能障碍的反馈与调节Nrf2和NF-kappa B协调活动的炎症信号通路失调之间的联系。此外，我们的研究表明，将CBP关联从NF-kappa B转移到Nrf2的策略可能具有减少CF患者炎症的潜在治疗效果。
Ziady AG, Sokolow A, Shank S, Corey D, Myers R, Plafker S, Kelley TJ. Interaction with CREB binding protein modulates the activities of Nrf2 and NF-kappa B in cystic fibrosis airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 302: L1221-L1231, 2012. First published March 30, 2012; doi: 10.1152/ajplung.00156.2011.-Cystic fibrosis (CF) is characterized by inflammatory lung disease that significantly contributes to morbidity and mortality. Airway epithelial cells play a role in the inflammatory signaling in CF and have been reported to exhibit a number of dysfunctions in signaling cascades that modulate inflammation. Previously, we reported that the activity of nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective protein expression, is diminished in CF epithelia (7). In this report, we examined the mechanism of Nrf2 dysregulation in vitro in human airway epithelial cell lines and primary cells and in vivo in nasal epithelia excised from Delta F508 CF mutant mice. We found that cAMP-mediated signaling markedly reduces Nrf2 activity in CF vs. non-CF cells. Rp-cAMPS, a cAMP competitor, significantly corrected Nrf2 activity in CF cells, predominantly by increasing the nuclear accumulation of the transcription factor. Furthermore, we found that Rp-cAMPS significantly decreased NF-kappa B activation following inflammatory stimulation of CF cells. Further investigation revealed that Nrf2 and NF-kappa B compete for the transcriptional coactivator cAMP responsive element-binding protein (CREB) binding protein (CBP) and that Rp-cAMPS shifts CBP association in favor of Nrf2. Thus our findings provide a link between feedback to CF transmembrane regulator dysfunction and dysregulation of an inflammatory signaling pathway that modulates the coordinated activities of Nrf2 and NF-kappa B. Furthermore, our studies suggest that strategies that shift CBP association away from NF-kappa B and toward Nrf2 could have potential therapeutic efficacy for reducing inflammation in patients with CF.