title: Exaggerated apoptosis and NF-kappaB activation in pancreatic and tracheal cystic fibrosis cells.
abstract: The pathophysiologic mechanisms causing inflammation in cystic fibrosis (CF) remain obscure. The effects of proapoptotic agents on pancreatic and tracheal cell lines expressing wild-type CFTR (PANC-1 and NT-1, respectively) or the homozygous CFTRDeltaF508 mutation (CFPAC-1 and CFT-2, respectively) were assessed. An increased susceptibility to apoptosis was observed in CFPAC-1 and CFT-2 cells. Apoptosis was reduced by treatment with a pan-caspase inhibitor and by incubation at 27 degrees C, allowing recruitment of CFTR deltaF508 at the plasma membrane. Inhibition of CFTR function in wild-type cells induced an increase of apoptosis. Apoptosis in CFPAC-1, but not in CFT-2 cells, was associated with overexpression of the proinflammatory mediators interleukin-6 and interleukin-8. In CF cells, apoptosis was linked to NF-kappaB pathway activation. Conditioned medium from actinomycin D-treated CFPAC-1 cells produced an increase in apoptosis of wild-type cells, suggesting that proinflammatory mediators secreted by mutant cells promote apoptosis. This was confirmed through the induction of apoptosis in wild-type cells by exogenous interleukin-6 and interleukin-8. These results suggest that CFTR deltaF508 mutation, apoptosis, and activation of the NF-kappaB pathway contribute to the self-perpetuating inflammatory cycle, at least in pancreatic cells, and provide evidence that excessive apoptosis may account for the exaggerated proinflammatory response observed in CF patients.
authors: INSERM, U770, Le Kremlin-Bicêtre, France.
authors: Mathilde
authors: M
authors: Rottner
authors: Corinne
authors: C
authors: Kunzelmann
authors: Martine
authors: M
authors: Mergey
authors: Jean-Marie
authors: JM
authors: Freyssinet
authors: María Carmen
authors: MC
authors: Martínez
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D014132:Trachea / Q000166:cytology / Q000378:metabolism*
chemical_list: C505032:CFTR protein, human; D017077:Culture Media, Conditioned; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D020169:Caspases