title: Legionella pneumophila-induced PKCalpha-, MAPK-, and NF-kappaB-dependent COX-2 expression in human lung epithelium.
abstract: Legionella pneumophila causes community- and hospital-acquired pneumonia. Lung airway and alveolar epithelial cells comprise an important barrier against airborne pathogens. Cyclooxygenase (COX) and microsomal PGE(2) synthase-1 (mPGES-1)-derived prostaglandins like prostaglandin E(2) (PGE(2)) are considered as important regulators of lung function. Herein we tested the hypothesis that L. pneumophila induced COX-2 and mPGES-1-dependent PGE(2) production in pulmonary epithelial cells. Legionella induced the release of PGE(2) in primary human small airway epithelial cells and A549 cells. This was accompanied by an increased expression of COX-2 and mPGES-1 as well as an increased PLA(2) activity in infected cells. Deletion of the type IV secretion system Dot/Icm did not impair Legionella-related COX-2 expression or PGE(2) release in A549 cells. L. pneumophila induced the degradation of IkappaBalpha and activated NF-kappaB. Inhibition of IKK blocked L. pneumophila-induced PGE(2) release and COX-2 expression. We noted activation of p38 and p42/44 MAP kinase in Legionella-infected A549 cells. Moreover, membrane translocation and activation of PKCalpha was observed in infected cells. PKCalpha and p38 and p42/44 MAP kinase inhibitors reduced PGE(2) release and COX-2 expression. In summary, PKCalpha and p38 and p42/44 MAP kinase controlled COX-2 expression and subsequent PGE(2) release by Legionella-infected lung epithelial cells. These pathways may significantly contribute to the host response in Legionnaires' disease.
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Philippe Dje
authors.initials: PD
authors.lastname: N'Guessan
authors.forename: Mirabelle O
authors.initials: MO
authors.lastname: Etouem
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmeck
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Hocke
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scharf
authors.forename: Kremena
authors.initials: K
authors.lastname: Vardarova
authors.forename: Bastian
authors.initials: B
authors.lastname: Opitz
authors.forename: Antje
authors.initials: A
authors.lastname: Flieger
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D016952:Legionella pneumophila / Q000472:pathogenicity*; D007877:Legionnaires' Disease / Q000209:etiology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology*; D008565:Membrane Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D051571:Protein Kinase C-alpha / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D008565:Membrane Proteins; D016328:NF-kappa B; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D010741:Phospholipases A; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone