title: Histone acetylation and flagellin are essential for Legionella pneumophila-induced cytokine expression.
abstract: 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.
authors.affiliation: FORSYS Junior Research Group, Systems Biology of Lung Inflammation, Charité-Universitätsmedizin, Berlin, Germany. Bernd.Schmeck@charite.de
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmeck
authors.forename: Janina
authors.initials: J
authors.lastname: Lorenz
authors.forename: Philippe Dje
authors.initials: PD
authors.lastname: N'guessan
authors.forename: Bastian
authors.initials: B
authors.lastname: Opitz
authors.forename: Vincent
authors.initials: V
authors.lastname: van Laak
authors.forename: Janine
authors.initials: J
authors.lastname: Zahlten
authors.forename: Hortense
authors.initials: H
authors.lastname: Slevogt
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.forename: Antje
authors.initials: A
authors.lastname: Flieger
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
mesh_terms: D000107:Acetylation; D048729:Anacardic Acids / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D005408:Flagellin / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016952:Legionella pneumophila / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D012319:RNA Polymerase II / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048729:Anacardic Acids; D004791:Enzyme Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D016209:Interleukin-8; D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D005408:Flagellin; C088115:anacardic acid; C012589:trichostatin A; D051548:Histone Acetyltransferases; D048051:p38 Mitogen-Activated Protein Kinases; D012319:RNA Polymerase II; D006655:Histone Deacetylases