Legionella pneumophila causes severe
pneumonia. Acetylation of
histones is thought to be an important regulator of gene transcription, but its impact on L. pneumophila-induced expression of proinflammatory
cytokines is unknown. L. pneumophila strain 130b induced the expression of the important
chemoattractant IL-8 and genome-wide histone modifications in human lung epithelial A549 cells. We analyzed the IL-8-promoter and found that
histone H4 was acetylated and H3 was phosphorylated at Ser(10) and acetylated at Lys(14), followed by
transcription factor NF-kappaB. Recruitment of
RNA polymerase II to the
IL-8 promoter corresponded with increases in gene transcription.
Histone modification and
IL-8 release were dependent on p38
kinase and
NF-kappaB pathways. Legionella-induced
IL-8 expression was decreased by
histone acetylase (HAT) inhibitor
anacardic acid and enhanced by
histone deacetylase (
HDAC) inhibitor trichostatin A. After Legionella
infection, HATs p300 and
CREB-binding protein were time-dependently recruited to the
IL-8 promoter, whereas HDAC1 and HDAC5 first decreased and later reappeared at the promoter. Legionella specifically induced expression of HDAC5 but not of other HDACs in lung epithelial cells, but knockdown of HDAC1 or 5 did not alter
IL-8 release. Furthermore, Legionella-induced
cytokine release, promoter-specific histone modifications, and
RNA polymerase II recruitment were reduced in
infection with
flagellin-deletion mutants. Legionella-induced
histone modification as well as HAT-/HDAC-dependent
IL-8 release could also be shown in primary lung epithelial cells. In summary,
histone acetylation seems to be important for the regulation of proinflammatory gene expression in L. pneumophila infected lung epithelial cells. These pathways may contribute to the host response in
Legionnaires' disease.