title: Activation of NF-kappaB in airway epithelial cells is dependent on CFTR trafficking and Cl- channel function.
abstract: Polymorphonuclear leukocyte-dominated airway inflammation is a major component of cystic fibrosis (CF) lung disease and may be associated with CF transmembrane conductance regulator (CFTR) dysfunction as well as infection. Mutant DeltaF508 CFTR is mistrafficked, accumulates in the endoplasmic reticulum (ER), and may cause "cell stress" and activation of nuclear factor (NF)-kappaB. G551D mutants also lack Cl- channel function, but CFTR is trafficked normally. We compared the effects of CFTR mutations on the endogenous activation of an NF-kappaB reporter construct. In transfected Chinese hamster ovary cells, the mistrafficked DeltaF508 allele caused a sevenfold activation of NF-kappaB compared with wild-type CFTR or the G551D mutant (P < 0.001). NF-kappaB was also activated in 9/HTEo-/pCep-R cells and in 16HBE/pcftr antisense cell lines, which lack CFTR Cl- channel function but do not accumulate mutant protein in the ER. This endogenous activation of NF-kappaB was associated with elevated interleukin-8 expression. Impaired CFTR Cl- channel activity as well as cell stress due to accumulation of mistrafficked CFTR in the ER contributes to the endogenous activation of NF-kappaB in cells with the CFTR mutation.
authors.affiliation: College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Weber
authors.forename: G
authors.initials: G
authors.lastname: Soong
authors.forename: R
authors.initials: R
authors.lastname: Bryan
authors.forename: S
authors.initials: S
authors.lastname: Saba
authors.forename: A
authors.initials: A
authors.lastname: Prince
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018118:Chloride Channels / Q000502:physiology*; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000378:metabolism; D012016:Reference Values; D014132:Trachea / Q000378:metabolism*
chemical_list: C505032:CFTR protein, human; D018118:Chloride Channels; D016209:Interleukin-8; D016328:NF-kappa B; D010446:Peptide Fragments; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002118:Calcium