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

¹ Dept of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
² Dept of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; and Institute for Periodontology and Synoptic Dentistry, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
³ NG5 Pathogenesis of Legionella Infection, Robert Koch-Institut, Berlin, 13353 Berlin, Germany

^* To whom correspondence should be addressed. E-mail: stefan.hippenstiel{at}charite.de.

	Abstract

Legionella pneumophila causes community-acquired pneumonia with high mortality, but little is known about its interaction with alveolar epithelium. We tested whether L. pneumophila-infection of lung epithelial cells (A549) resulted in proinflammatory activation.

L. pneumophila-infection induced liberation of IL-2, IL-4, IL-6, IL-8, IL-17, MCP-1, TNF, IL-1, IFN, G-CSF, but not of IL-5, IL-7, IL-10, IL-12 (p70), IL-13 or GM-CSF. We focused on IL-8 and found induction by L. pneumophila strains 130b, Philadelphia 1, Corby, and to a lower extent, JR32. Knock out 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 MAP kinase was activated and kinase inhibition reduced secretion of of induced cytokines with exception of IL-2 and G-CSF. In contrast, inhibition of MEK1/ERK pathway only reduced expression of few cytokines. L. pneumophila also induced binding of NF-B subunit RelA/p65 and the RNA polymerase II to the il8 promoter and a specific inhibitor of the IB- complex dose-dependently lowered IL-8 expression.

Taken together, L. pneumophila activated p38 MAP kinase- and NF-B/RelA pathway-dependent expression of a complex pattern of cytokines by human alveolar epithelial cells, presumably contributing to immune response in Legionellosis.

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