title: Mechanisms of Chlamydophila pneumoniae-mediated GM-CSF release in human bronchial epithelial cells.
abstract: Chlamydophila pneumoniae is an important respiratory pathogen. In this study we characterized C. pneumoniae strain TW183-mediated activation of human small airway epithelial cells (SAEC) and the bronchial epithelial cell line BEAS-2B and demonstrated time-dependent secretion of granulocyte macrophage colony-stimulating factor (GM-CSF) upon stimulation. TW183 activated p38 mitogen-activated protein kinase (MAPK) in epithelial cells. Kinase inhibition by SB202190 blocked Chlamydia-mediated GM-CSF release on mRNA and protein levels. In addition, the chemical inhibitor as well as dominant-negative mutants of p38 MAPK isoforms p38alpha, beta2, and gamma inhibited C. pneumoniae-related NF-kappaB activation. In contrast, blocking of MAPK ERK, c-Jun kinase/JNK, or PI-3 Kinase showed no effect on Chlamydia-related epithelial cell GM-CSF release. Ultraviolet-inactivated pathogens as compared with viable bacteria induced a smaller GM-CSF release, suggesting that viable Chlamydiae were only partly required for a full effect. Presence of an antichlamydial outer membrane protein-A (OmpA) antibody reduced and addition of recombinant heat-shock protein 60 from C. pneumoniae (cHsp60, GroEL-1)-enhanced GM-CSF release, suggesting a role of these proteins in epithelial cell activation. Our data demonstrate that C. pneumoniae triggers an early proinflammatory signaling cascade involving p38 MAPK-dependent NF-kappaB activation, resulting in subsequent GM-CSF release. C. pneumoniae-induced epithelial cytokine liberation may contribute significantly to inflammatory airway diseases like chronic obstructive pulmonary disease (COPD) or bronchial asthma.
authors.affiliation: Department of Internal Medicine/Infectious Diseases, Charité, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. matthias.kruell@charite.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Krüll
authors.forename: Petra
authors.initials: P
authors.lastname: Bockstaller
authors.forename: Frederik N
authors.initials: FN
authors.lastname: Wuppermann
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Klucken
authors.forename: Jörg
authors.initials: J
authors.lastname: Mühling
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmeck
authors.forename: Joachim
authors.initials: J
authors.lastname: Seybold
authors.forename: Clemens
authors.initials: C
authors.lastname: Walter
authors.forename: Matthias
authors.initials: M
authors.lastname: Maass
authors.forename: Simone
authors.initials: S
authors.lastname: Rosseau
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Hegemann
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000378:metabolism; D016993:Chlamydophila pneumoniae / Q000502:physiology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000382:microbiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D018834:Chaperonin 60; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007093:Imidazoles; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; C078167:OMPA outer membrane proteins; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole