Simvastatin reduces Chlamydophila pneumoniae-mediated histone modifications and gene expression in cultured human endothelial cells.
Inflammatory activation of the endothelium by Chlamydophila pneumoniae infection has been implicated in the development of chronic vascular lesions and coronary heart disease by seroepidemiological and animal studies. We tested the hypothesis that C. pneumoniae induced inflammatory gene expression is regulated by Rho-GTPase-related histone modifications. C. pneumoniae infection induced the liberation of proinflammatory interleukin-6, interleukin-8, granulocyte colony-stimulating factor, macrophage inflammatory protein-1beta, granulocyte/macrophage colony-stimulating factor, and interferon-gamma by human endothelial cells. Cytokine secretion was reduced by simvastatin and the specific Rac1 inhibitor NSC23766 but was synergistically enhanced by inhibitors of histone deacetylases trichostatin A and suberoylanilide hydroxamic acid. Infection of endothelial cells with viable C. pneumoniae, but not exposure to heat-inactivated C. pneumoniae or infection with C. trachomatis, induced acetylation of histone H4 and phosphorylation and acetylation of histone H3. Pretreatment of C. pneumoniae-infected cells with simvastatin or NSC23766 reduced global histone modifications as well as specific modifications at the il8 gene promoter, as shown by chromatin immunoprecipitation. Reduced recruitment of nuclear factor kappaB p65/RelA as well as of RNA polymerase II was observed in statin-treated cells. Taken together, Rac1-mediated histone modifications seem to play an important role in C. pneumoniae-induced cytokine production by human endothelial cells.
Schmeck
Bernd
B
Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, FORSYS Junior Research Group Systems Biology of Lung Inflammation, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. bernd.schmeck@charite.de
Beermann
Wiebke
W
N'Guessan
Philippe Dje
PD
Hocke
Andreas C
AC
Opitz
Bastian
B
Eitel
Julia
J
Dinh
Quoc Thai
QT
Witzenrath
Martin
M
Krüll
Matthias
M
Suttorp
Norbert
N
Hippenstiel
Stefan
S
D002478:Cells, Cultured; D016993:Chlamydophila pneumoniae / Q000187:drug effects / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D042783:Endothelial Cells / Q000382:microbiology; D015870:Gene Expression / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D019821:Simvastatin / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D016207:Cytokines; D006657:Histones; D019821:Simvastatin; D020830:rac1 GTP-Binding Protein