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F508 mutation on prostaglandin E2production and type-IIA phospholipase A2 expression by pulmonary epithelial cells
1 Unite de Defense Innee et Inflammation, Institut Pasteur, Paris, France, Metropolitan
* To whom correspondence should be addressed. E-mail: touqui{at}pasteur.fr.
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 showed 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 an enhanced expression and activity of cyclooxygenase-2 (COX-2) in CF cells. PGE2 release was attenuated after experimentally-induced re-trafficking 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 to control cells and was enhanced by LPS. However, addition of PGE2or aspirin had no effect on NF-B activation. LPS-induced sPLA2-IIA expression was reduced by a 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 up-regulated by NF-B and amplified by PGE2 via a non identified signalling pathway.
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