Impact of CFTR DeltaF508 mutation on prostaglandin E2 production and type IIA phospholipase A2 expression by pulmonary epithelial cells.
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 DeltaF508 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 DeltaF508-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-kappaB 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-kappaB activation. LPS-induced sPLA2-IIA expression was reduced by an NF-kappaB 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-kappaB and amplified by PGE2 via a unidentified signaling pathway.
Medjane
Samir
S
Institut Pasteur, Unité de Défense Innée et Inflammation; and Institut National de la Santé et de la Recherche Médicale, E336, Paris, France.
Raymond
Benoit
B
Wu
Yongzheng
Y
Touqui
Lhousseine
L
D001483:Base Sequence; D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004247:DNA / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D054501:Group II Phospholipases A2; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D010741:Phospholipases A / Q000235:genetics*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014132:Trachea / Q000378:metabolism / Q000473:pathology
C505032:CFTR protein, human; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004247:DNA; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D015232:Dinoprostone