Interaction with CREB binding protein modulates the activities of Nrf2 and NF-κB in cystic fibrosis airway epithelial cells

• Authors: Assem Ziady, Emory University; Andrew Sokolow, Case Western Reserve University; Samuel Shank, Case Western Reserve University; Deborah Corey, Case Western Reserve University; Ross Myers, Case Western Reserve University; Scott Plafker, The Oklahoma Medical Research Foundation; Thomas J. Kelley, Case Western Reserve University
• Journal Title: American Journal of Physiology - Lung Cellular and Molecular Physiology
• Volume: Volume 302, Number 11
• Publisher: American Physiological Society | 2012-06-01, Pages L1221-L1231
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1152/ajplung.00156.2011
• Keywords: H2O2-mediated inflammatory signaling; airway epithelia; cAMP responsive element-binding protein

Abstract

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 ΔF508 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-κB activation following inflammatory stimulation of CF cells. Further investigation revealed that Nrf2 and NF-κB 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-κB. Furthermore, our studies suggest that strategies that shift CBP association away from NF-κB and toward Nrf2 could have potential therapeutic efficacy for reducing inflammation in patients with CF.