title: Reduced expression of Tis7/IFRD1 protein in murine and human cystic fibrosis airway epithelial cell models homozygous for the F508del-CFTR mutation.
abstract: 12-O-tetradecanoyl phorbol-13-acetate-induced sequence 7/interferon related development regulator 1 (Tis7/IFRD1) has been recently identified as a modifier gene in lung inflammatory disease severity in patients with cystic fibrosis (CF), based upon its capacity to regulate inflammatory activities in neutrophils. In CF patients, the F508del mutation in the Cftr gene encoding a chloride channel, the CF transmembrane conductance regulator (CFTR) in airway epithelial cells results in an exaggerated inflammatory response of these cells. At present, it is unknown whether the Tis7/IFRD1 gene product is expressed in airway epithelial cells. We therefore investigated the possibility there is an intrinsic alteration in Tis7/IFRD1 protein level in cells lacking CFTR function in tracheal homogenates of F508del-CFTR mice and in a F508del-CFTR human bronchial epithelial cell line (CFBE41o(-) cells). When Tis7/IFRD1 protein was detectable, trachea from F508del-CFTR mice showed a reduction in the level of Tis7/IFRD1 protein compared to wild-type control littermates. A significant reduction of IFRD1 protein level was found in CFBE41o(-) cells compared to normal bronchial epithelial cells 16HBE14o(-). Surprisingly, messenger RNA level of IFRD1 in CFBE41o(-) cells was found elevated. Treating CFBE41o(-) cells with the antioxidant glutathione rescued the IFRD1 protein level closer to control level and also reduced the pro-inflammatory cytokine IL-8 release. This work provides evidence for the first time of reduced level of IFRD1 protein in murine and human F508del-CFTR airway epithelial cell models, possibly mediated in response to oxidative stress which might contribute to the exaggerated inflammatory airway response observed in CF patients homozygous for the F508del mutation.
authors: Cdr St-Antoine, Inserm UMR-S U 938, Paris F-75012, France.
authors: Elise
authors: E
authors: Blanchard
authors: Solenne
authors: S
authors: Marie
authors: Laure
authors: L
authors: Riffault
authors: Monique
authors: M
authors: Bonora
authors: Olivier
authors: O
authors: Tabary
authors: Annick
authors: A
authors: Clement
authors: Jacky
authors: J
authors: Jacquot
mesh_terms: D000818:Animals; D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000096:biosynthesis; D056464:Histone Deacetylase 2 / Q000096:biosynthesis; D006720:Homozygote; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D018181:Mice, Inbred CFTR; D020545:Respiratory Mucosa / Q000378:metabolism*; D017384:Sequence Deletion
chemical_list: C490045:IFRD1 protein, human; C490044:Ifrd1 protein, mouse; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2