Legionella pneumophila-induced IκBζ-dependent expression of interleukin-6 in lung epithelium.
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.
Lorenz
J
J
Dept of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Zahlten
J
J
Pollok
I
I
Lippmann
J
J
Scharf
S
S
N'Guessan
P D
PD
Opitz
B
B
Flieger
A
A
Suttorp
N
N
Hippenstiel
S
S
Schmeck
B
B
D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D005408:Flagellin / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D016952:Legionella pneumophila / Q000378:metabolism*; D007876:Legionellosis / Q000378:metabolism / Q000382:microbiology*; D008168:Lung / Q000378:metabolism / Q000382:microbiology*; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism; D011401:Promoter Regions, Genetic
D002843:Chromatin; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D005408:Flagellin; D051550:I-kappa B Kinase