title: CFTR negatively regulates cyclooxygenase-2-PGE(2)  positive feedback loop in inflammation.
abstract: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent anion channel mostly expressed in epithelia. Accumulating evidence suggests that CF airway epithelia are overwhelmed by excessive inflammatory cytokines and prostaglandins (PGs), which eventually lead to the over-inflammatory condition observed in CF lung disease. However, the exact underlying mechanism remains elusive. In this study, we observed increased cyclooxygenase-2 (COX-2) expression and over-production of prostaglandin E(2) (PGE(2)) in human CF bronchial epithelia cell line (CFBE41o--) with elevated NF-κB activity compared to a wild-type airway epithelial cell line (16HBE14o--). Moreover, we demonstrated that CFTR knockout mice had inherently higher levels of COX-2 and NF-κB activity, supporting the notion that lack of CFTR results in hyper-inflammatory signaling. In addition, we identified a positive feedback loop for production of PGE(2) involving PKA and transcription factor, CREB. More importantly, overexpression of wild-type CFTR significantly suppressed COX-2 expression in CFBE41o- cells, and wild-type CFTR protein expression was significantly increased when 16HBE14o-- cells were challenged with LPS as well as PGE(2), indicating possible involvement of CFTR in negative regulation of COX-2/PGE(2). In conclusion, CFTR is a negative regulator of PGE(2)-mediated inflammatory response, defect of which may result in excessive activation of NF-κB, leading to over production of PGE(2) as seen in inflammatory CF tissues.
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Xiao Hua
authors.initials: XH
authors.lastname: Jiang
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Jing Hui
authors.initials: JH
authors.lastname: Guo
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.forename: Mei Kuen
authors.initials: MK
authors.lastname: Yu
authors.forename: Wen Ming
authors.initials: WM
authors.lastname: Xu
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D006801:Humans; D051379:Mice; D018181:Mice, Inbred CFTR; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000382:microbiology; D012141:Respiratory Tract Infections / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology; D013997:Time Factors; D014162:Transfection
chemical_list: C505032:CFTR protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone