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Impact of CFTR F508 mutation on prostaglandin E₂ production and type IIA phospholipase A₂ expression by pulmonary epithelial cells

Institut Pasteur, Unité de Défense Innée et Inflammation; and Institut National de la Santé et de la Recherche Médicale, E336, Paris, France

Submitted 15 December 2004 ; accepted in final form 14 June 2005

Cystic fibrosis (CF) is characterized by an exacerbated inflammatory pulmonary response with excessive production of inflammatory mediators. We investigated here the impact of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction on prostaglandin E₂ (PGE₂) production and type IIA secreted phospholipase A₂ (sPLA₂-IIA) expression. We show that both resting and LPS-stimulated human respiratory epithelial cell line bearing F508 mutation on CFTR (CF cells) released more PGE₂ than control cell line. This was accompanied by enhanced expression and activity of cyclooxygenase-2 in CF cells. PGE₂ release was attenuated after experimentally induced retrafficking of the F508-CFTR at the plasma membrane. sPLA₂-IIA expression occurred at higher levels in CF cells than in control cells and was enhanced by LPS and PGE₂. Suppression of PGE₂ synthesis by aspirin led to an inhibition of LPS-induced sPLA₂-IIA expression. Higher activation of NF-B was observed in CF cells compared with control cells and was enhanced by LPS. However, addition of PGE₂ or aspirin had no effect on NF-B activation. LPS-induced sPLA₂-IIA expression was reduced by an NF-B inhibitor. We suggest that the lack of the CFTR in the plasma membrane results in a PGE₂ overproduction and an enhanced sPLA₂-IIA expression. This expression is upregulated by NF-B and amplified by PGE₂ via a unidentified signaling pathway.

cystic fibrosis; inflammation; arachidonic acid metabolism; cystic fibrosis transmembrane conductance regulator

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