Abstract
Legionella pneumophila causes severe community- and hospital-acquired pneumonia. Lung airway and alveolar epithelial cells comprise an important sentinel system in airborne infections. Although interleukin-6 (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 to IL-8 by human lung epithelial cells. IL-6 expression depended at early time points on flagellin recognition by TLR5, activity of MEK1 and p38 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 NF-κB subunit p50 - recruited to the il6 promoter together with C/EBPβ and phosphorylated AP-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 remodeling and subsequent IL-6 transcription in L. pneumophila-infected lung epithelial cells.
- ERS