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Legionella pneumophila-induced NF-B- and MAPK-dependent cytokine release by lung epithelial cells

¹ Dept of Internal Medicine/Infectious Diseases and Respiratory Medicine and ² Institute for Periodontology and Synoptic Dentistry, Charité – Universitätsmedizin Berlin, and ³ Nachwuchsgruppe 5 Pathogenesis of Legionella Infection, Robert Koch Institute, Berlin, Germany.

CORRESPONDENCE: S. Hippenstiel, Dept of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Fax: 49 30450553906. E-mail: stefan.hippenstiel{at}charite.de

Keywords: Alveolar epithelium, bacteria, cytokines, signal transduction pathways

Received: November 30, 2005
Accepted August 7, 2006

Legionella pneumophila causes community-acquired pneumonia with high mortality, but little is known about its interaction with the alveolar epithelium. The aim of this study was to investigate whether L. pneumophila infection of lung epithelial cells (A549) resulted in pro-inflammatory activation.

L. pneumophila infection induced liberation of interleukin (IL)-2, -4, -6, -8 and -17, monocyte chemoattractant protein-1, tumour necrosis factor-, IL-1ß, interferon- and granulocyte colony-stimulating factor, but not of IL-5, -7, -10, -12 (p70) or -13 or granulocyte-macrophage colony-stimulating factor. The present study focused on IL-8 and found induction by L. pneumophila strains 130b, Philadelphia 1, Corby and, to a lesser extent, JR32. Knockout of dotA, a central gene involved in type IVB secretion, did not alter IL-8 induction, whereas lack of flagellin significantly reduced IL-8 release by Legionella. Moreover, p38 mitogen-activated protein kinase (MAPK) was activated and kinase inhibition reduced secretion of induced cytokines, with the exception of IL-2 and granulocyte colony-stimulating factor. In contrast, inhibition of the MAPK kinase 1/extracellular signal-regulated kinase pathway only reduced the expression of a few cytokines. L. pneumophila also induced binding of nuclear factor-B subunit RelA/p65 and RNA polymerase II to the il8 promoter, and a specific inhibitor of the inhibitor of nuclear factor-B complex dose-dependently lowered IL-8 expression.

Taken together, Legionella pneumophila activated p38 mitogen-activated protein kinase- and nuclear factor-B/RelA pathway-dependent expression of a complex pattern of cytokines by human alveolar epithelial cells, presumably contributing to the immune response in legionellosis.

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