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Exaggerated apoptosis and NF-B activation in pancreatic and tracheal cystic fibrosis cells

Mathilde Rottner^*,, Corinne Kunzelmann^*,, Martine Mergey, Jean-Marie Freyssinet^*, and María Carmen Martínez^*,,1

^* INSERM, U770, Le Kremlin-Bicêtre, France; Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, le Kremlin-Bicêtre, France;

Université Louis Pasteur, Faculté de Médecine, Institut d'Hématologie et d'Immunologie, Strasbourg, France;

INSERM, U680, Paris, France; and Université Pierre et Marie Curie, Site Saint-Antoine, Paris, France

¹Correspondence: CNRS UMR 6214-INSERM U771, Faculté de Médecine, rue Haute de Reculée, 49045 Angers, France. E-mail: carmen.martinez{at}univ-angers.fr

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 CFTRF508 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 CFTRF508 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-B 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 CFTRF508 mutation, apoptosis, and activation of the NF-B 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-B activation in pancreatic and tracheal cystic fibrosis cells.

Key Words: CFTR • phosphatidylserine • inflammation • cytokines