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Defective CFTR- ?-catenin interaction promotes NF-?B nuclear translocation and intestinal inflammation in cystic fibrosis.

ABSTRACT: While inflammation with aberrant activation of NF-?B pathway is a hallmark of cystic fibrosis (CF), the molecular mechanisms underlying the link between CFTR defect and activation of NF-?B-mediated pro-inflammatory response remain elusive. Here, we investigated the link between CFTR defect and NF-?B activation in ?F508cftr-/- mouse intestine and human intestinal epithelial cell lines. Our results show that the NF-?B/COX-2/PGE2 pathway is activated whereas the ?-catenin pathway is suppressed in CF mouse intestine and CFTR-knockdown cells. Activation of ?-catenin pathway by GSK3 inhibitors suppresses CFTR mutation/knockdown-induced NF-?B/COX-2/PGE2 pathway in ?F508 mouse intestine and CFTR-knockdown cells. In contrast, suppression of ?-catenin signaling induces the nuclear translocation of NF-?B. In addition, CFTR co-localizes and interacts with ?-catenin while CFTR mutation disrupts the interaction between NF-?B and ?-catenin in mouse intestine. Treatment with proteasome inhibitor MG132 completely reverses the reduced expression of ?-catenin in Caco-2 cells. Collectively, these results indicate that CFTR stabilizes ?-catenin and prevents its degradation, defect of which results in the activation of NF-?B-mediated inflammatory cascade. The present study has demonstrated a previously unsuspected interaction between CFTR and ?-catenin that regulates NF-?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-?B-mediated intestinal inflammation seen in CF.

SUBMITTER: Liu K

PROVIDER: S-EPMC5325423 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Liu Kaisheng K Zhang Xiaohu X Zhang Jie Ting JT Tsang Lai Ling LL Jiang Xiaohua X Chan Hsiao Chang HC

Oncotarget 20160901 39

While inflammation with aberrant activation of NF-κB pathway is a hallmark of cystic fibrosis (CF), the molecular mechanisms underlying the link between CFTR defect and activation of NF-κB-mediated pro-inflammatory response remain elusive. Here, we investigated the link between CFTR defect and NF-κB activation in ΔF508cftr-/- mouse intestine and human intestinal epithelial cell lines. Our results show that the NF-κB/COX-2/PGE2 pathway is activated whereas the β-catenin pathway is suppressed in C ...[more]

PMID: 27588407

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Project description:UnlabelledCystic fibrosis-associated liver disease is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing biliary chloride and bicarbonate secretion, up-regulation of toll-like receptor 4/nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB)-dependent immune mechanisms plays a major role in the pathogenesis of cystic fibrosis-associated liver disease and may represent a therapeutic target. Nuclear receptors are transcription factors that regulate several intracellular functions. Some nuclear receptors, including peroxisome proliferator-activated receptor-γ (PPAR-γ), may counterregulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-γ stimulation in vivo in cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice exposed to dextran sodium sulfate and in vitro in primary cholangiocytes isolated from wild-type and from Cftr-knockout mice exposed to lipopolysaccharide. We found that in CFTR-defective biliary epithelium expression of PPAR-γ is increased but that this does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR-γ (pioglitazone and rosiglitazone) up-regulates PPAR-γ-dependent genes, while inhibiting the activation of NF-κB and the secretion of proinflammatory cytokines (lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, granulocyte colony-stimulating factor, keratinocyte chemoattractant) in response to lipopolysaccharide. PPAR-γ agonists modulate NF-κB-dependent inflammation by up-regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF-κB. Stimulation of PPAR-γ in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr-knockout mice exposed to a dextran sodium sulfate-induced portal endotoxemia.ConclusionThese studies unravel a novel function of PPAR-γ in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR-γ contributes to the chronic inflammatory state of CFTR-defective cholangiocytes.

Dataset Information

Defective CFTR- ?-catenin interaction promotes NF-?B nuclear translocation and intestinal inflammation in cystic fibrosis.

Publications

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

Similar Datasets

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