Exaggerated apoptosis and NF‐KB activation in pancreatic and tracheal cystic fibrosis cells

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 CFTR∆F508 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°C, allowing recruitment of CFTR∆F508 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 inter‐leukin‐6 and interleukin‐8. In CF cells, apoptosis was linked to NF‐KB 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 interleu‐kin‐6 and interleukin‐8. These results suggest that CFTR∆F508 mutation, apoptosis, and activation of the NF‐KB 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.—Rottner, R., Kunzelmann, C., Mergey, M., Freyssinet, J‐M., Martínez, M. C. Exaggerated apoptosis and NF‐KB activation in pancreatic and tracheal cystic fibrosis cells. FASEB J. 21, 2939–2948 (2007)