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Histone Acetylation and Flagellin Are Essential for Legionella pneumophila-Induced Cytokine Expression¹

Bernd Schmeck^2,3,*,, Janina Lorenz^3,, Philippe Dje N'Guessan, Bastian Opitz, Vincent van Laak, Janine Zahlten, Hortense Slevogt, Martin Witzenrath, Antje Flieger, Norbert Suttorp and Stefan Hippenstiel

^* FORSYS Junior Research Group "Systems Biology of Lung Inflammation," Charité–Universitätsmedizin, Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité–Universitätsmedizin, and NG5 Pathogenesis of Legionella Infection, Robert Koch-Institut, Berlin, Germany

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 Ser¹⁰ and acetylated at Lys¹⁴, followed by transcription factor NF-B. 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-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants of the Bundesministerium für Bildung und Forschung (BMBF) to B.S. (BMBF-Competence Network CAPNETZ C15, and BMBF-FORSYS-Partner), to S.H. (BMBF Network PROGRESS, DFG HI-789/6-1), to N.S. (BMBF-Competence Network CAPNETZ), and the Deutsche Gesellschaft für Pneumologie to J.Z., S.H., and B.O.

² Address correspondence and reprint requests to Dr. Bernd Schmeck, Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, FORSYS Junior Research Group "Systems Biology of Lung Inflammation," Charité–Universitätsmedizin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail address: Bernd.Schmeck{at}charite.de

³ B.S. and J.L. contributed equally.

⁴ Abbreviations used in this paper: HDAC, histone deacetylase; HAT, histone acetylase; IKK, IB kinase; TSA, trichostatin A; SAEC, small airway epithelial cell; ChIP, chromatin immunoprecipitation; Pol II, RNA polymerase II; siRNA, short silencing RNA; NBD, nemo binding domain; CBP, CREB-binding protein.