Abstract
Severe community- and hospital-acquired pneumonia is caused by Legionella pneumophila. Lung airway and alveolar epithelial cells comprise an important sentinel system in airborne infections. Although interleukin (IL)-6 is known as a central regulator of the immune response in pneumonia, its regulation in the lung is widely unknown.
Herein, we demonstrate that different L. pneumophila strains induce delayed expression of IL-6 in comparison with IL-8 by human lung epithelial cells. IL-6 expression depended, at early time points, on flagellin recognition by Toll-like receptor (TLR)5, activity of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1 and p38 mitogen-activated protein (MAP) kinase, and, at later time points, on the type-IV secretion system. In the same manner, but more rapidly, the recently described transcription factor IκBζ was induced by Legionella infection and, binding to the nuclear factor (NF)-κB subunit p50 - recruited to the il6 promoter together with CCAAT-enhancer-binding protein β and phosphorylated activator protein-1 subunit cJun. Similarly, histone modifications and NF-κB subunit p65/RelA appeared at the iκbζ and subsequently at the il6 gene promoter, thereby initiating gene expression. Gene silencing of IκBζ reduced Legionella-related IL-6 expression by 41%.
Overall, these data indicate a sequence of flagellin/TLR5- and type IV-dependent IκBζ expression, recruitment of IκBζ/p50 to the il6 promoter, chromatin remodelling and subsequent IL-6 transcription in L. pneumophila-infected lung epithelial cells.
Footnotes
This article has supplementary material available from www.erj.ersjournals.com
Support Statement
This work was supported by grants of the Bundesministerium für Bildung und Forschung and the Deutsche Forschungsgemeinschaft to B. Schmeck (BMBF-FORSYS-Partner “Forsys Lung” F-Kz 0315256, BMBF Network PROGRESS, DFG-SFB/TR84), J. Zahlten (BMBF Network PROGRESS, DFG-SFB/TR84), S. Hippenstiel (BMBF Network PROGRESS, DFG HI-789/6-1, DFG-SFB/TR84), N. Suttorp (BMBF Network PROGRESS, DFG-SFB/TR84), and the Charité – Universitätsmedizin Berlin to B. Schmeck.
Statement of Interest
None declared.
- Received December 19, 2009.
- Accepted June 26, 2010.
- ©ERS 2011