期刊
EUROPEAN RESPIRATORY JOURNAL
卷 37, 期 3, 页码 648-657出版社
EUROPEAN RESPIRATORY SOC JOURNALS LTD
DOI: 10.1183/09031936.00200009
关键词
Cytokines; gene regulation; Legionella; pneumonia; signal transduction
资金
- Bundesministerium fur Bildung und Forschung [F-Kz 0315256]
- Deutsche Forschungsgemeinschaft [DFG HI-789/6-1, DFG-SFB/TR84]
- Charite - Universitatsmedizin Berlin
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 I kappa B zeta was induced by Legionella infection and, binding to the nuclear factor (NF)-kappa B subunit p50 - recruited to the il6 promoter together with CCAAT-enhancer-binding protein beta and phosphorylated activator protein-1 subunit cJun. Similarly, histone modifications and NF-kappa B subunit p65/RelA appeared at the i kappa B zeta and subsequently at the il6 gene promoter, thereby initiating gene expression. Gene silencing of I kappa B zeta reduced Legionella-related IL-6 expression by 41%. Overall, these data indicate a sequence of flagellin/TLR5- and type IV-dependent I kappa B zeta expression, recruitment of I kappa B zeta/p50 to the il6 promoter, chromatin remodelling and subsequent IL-6 transcription in L. pneumophila-infected lung epithelial cells.
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