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 IkBf was induced by Legionella infection and, binding to the nuclear factor (NF)-kB subunit p50 -recruited to the il6 promoter together with CCAAT-enhancer-binding protein b and phosphorylated activator protein-1 subunit cJun. Similarly, histone modifications and NF-kB subunit p65/RelA appeared at the ikbf and subsequently at the il6 gene promoter, thereby initiating gene expression. Gene silencing of IkBf reduced Legionella-related IL-6 expression by 41%.Overall, these data indicate a sequence of flagellin/TLR5-and type IV-dependent IkBf expression, recruitment of IkBf/p50 to the il6 promoter, chromatin remodelling and subsequent IL-6 transcription in L. pneumophila-infected lung epithelial cells.

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