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Mechanisms of Chlamydophila pneumoniae–Mediated GM-CSF Release in Human Bronchial Epithelial Cells

Department of Internal Medicine/Infectious Diseases, Charité, Universitätsmedizin Berlin, Berlin; Institute of Microbiology, Heinrich-Heine-University, Düsseldorf; Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University, Giessen, Germany; and SALK Labor, Salzburger Landeskliniken, Salzburg, Austria

Correspondence and requests for reprints should be addressed to Matthias Krüll, M.D., Department of Internal Medicine/Infectious Diseases, Charité, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: matthias.kruell{at}charite.de

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 p38, ₂, and inhibited C. pneumoniae–related NF-B 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-B 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.

Key Words: Chlamydophila pneumoniae • epithelial cells • signal transduction • MAPK • inflammation

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