Legionella pneumophila-induced IκBζ-dependent expression of interleukin-6 in lung epithelium

Eur Respir J. 2011 Mar;37(3):648-57. doi: 10.1183/09031936.00200009. Epub 2010 Jul 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chromatin / metabolism
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology*
  • Flagellin / metabolism
  • Gene Expression Regulation*
  • Humans
  • I-kappa B Kinase / metabolism*
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Legionella pneumophila / metabolism*
  • Legionellosis / metabolism
  • Legionellosis / microbiology*
  • Lung / metabolism
  • Lung / microbiology*
  • NF-kappa B / metabolism
  • Pneumonia / metabolism
  • Promoter Regions, Genetic


  • Chromatin
  • Interleukin-6
  • Interleukin-8
  • NF-kappa B
  • Flagellin
  • I-kappa B Kinase