title: Intracellular bacteria differentially regulated endothelial cytokine release by MAPK-dependent histone modification.
abstract: Epigenetic histone modifications contribute to the regulation of eukaryotic gene transcription. The role of epigenetic regulation in immunity to intracellular pathogens is poorly understood. We tested the hypothesis that epigenetic histone modifications influence cytokine expression by intracellular bacteria. Intracellular Listeria monocytogenes, but not noninvasive Listeria innocua, induced release of distinct CC and CXC chemokines, as well as Th1 and Th2 cytokines and growth factors by endothelial cells. Cytokine expression was in part dependent on p38 MAPK and MEK1. We analyzed global histone modification and modifications in detail at the gene promoter of IL-8, which depended on both kinase pathways, and of IFN-gamma, which was not blocked by kinase inhibition. Intracellular Listeria induced time-dependent acetylation (lysine 8) of histone H4 and phosphorylation/acetylation (serine 10/lysine 14) of histone H3 globally and at the il8 promoter in HUVEC, as well as recruitment of the histone acetylase CREB-binding protein. Inhibitors of p38 MAPK and MEK1 reduced lysine 8 acetylation of histone H4 and serine 10/lysine 14 phosphorylation/acetylation of histone H3 in Listeria-infected endothelial cells and disappearance of histone deacetylase 1 at the il8 promoter in HUVEC. In contrast, IFN-gamma gene transcription was activated by Listeria monocytogenes independent of p38 MAPK and MEK1, and histone phosphorylation/acetylation remained unchanged in infected cells at the IFN-gamma promoter. Specific inhibition of histone deacetylases by trichostatin A increased Listeria-induced expression of IL-8, but not of IFN-gamma, underlining the specific physiological impact of histone acetylation. In conclusion, MAPK-dependent epigenetic modifications differentially contributed to L. monocytogenes-induced cytokine expression by human endothelial cells.
authors.affiliation: Department of Internal Medicine and Infectious Diseases, Charité-University Medicine Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmeck
authors.forename: Wiebke
authors.initials: W
authors.lastname: Beermann
authors.forename: Vincent
authors.initials: V
authors.lastname: van Laak
authors.forename: Janine
authors.initials: J
authors.lastname: Zahlten
authors.forename: Bastian
authors.initials: B
authors.lastname: Opitz
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Hocke
authors.forename: Trinad
authors.initials: T
authors.lastname: Chakraborty
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
authors.forename: Simone
authors.initials: S
authors.lastname: Rosseau
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
mesh_terms: D000107:Acetylation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000276:immunology*; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008089:Listeria monocytogenes / Q000472:pathogenicity*; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011401:Promoter Regions, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D016207:Cytokines; D006657:Histones; D016209:Interleukin-8; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases