Defective CFTR- β-catenin interaction promotes NF-κB nuclear translocation and intestinal inflammation in cystic fibrosis

While inflammation with aberrant activation of NF-kappa B pathway is a hallmark of cystic fibrosis (CF), the molecular mechanisms underlying the link between CFTR defect and activation of NF-kappa B-mediated pro-inflammatory response remain elusive. Here, we investigated the link between CFTR defect and NF-kappa B activation in Delta F508cftr(-/-) mouse intestine and human intestinal epithelial cell lines. Our results show that the NF-kappa B/COX-2/PGE(2) pathway is activated whereas the beta-catenin pathway is suppressed in CF mouse intestine and CFTR-knockdown cells. Activation of beta-catenin pathway by GSK3 inhibitors suppresses CFTR mutation/knockdown-induced NF-kappa B/COX-2/PGE(2) pathway in Delta F508 mouse intestine and CFTR-knockdown cells. In contrast, suppression of beta-catenin signaling induces the nuclear translocation of NF-kappa B. In addition, CFTR co-localizes and interacts with beta-catenin while CFTR mutation disrupts the interaction between NF-kappa B and beta-catenin in mouse intestine. Treatment with proteasome inhibitor MG132 completely reverses the reduced expression of beta-catenin in Caco-2 cells. Collectively, these results indicate that CFTR stabilizes beta-catenin and prevents its degradation, defect of which results in the activation of NF-kappa B-mediated inflammatory cascade. The present study has demonstrated a previously unsuspected interaction between CFTR and beta-catenin that regulates NF-kappa B nuclear translocation in mouse intestine. Therefore, our study provides novel insights into the physiological function of CFTR and pathogenesis of CF-related diseases in addition to the NF-kappa B-mediated intestinal inflammation seen in CF.