Visit our Expo - Redox and Inflammation signaling 2012

Listeria monocytogenes induced Rac1-dependent endothelial histone modification and
cytokine release
Bernd Schmeck*, Wiebke Beermann*, Vincent van Laak*, Bastian Opitz*, Andreas
Hocke*, Julia Eitel*, Trinad Chakraborty+, Gudula Schmidt#, Holger Barth#, Norbert
Suttorp*, and Stefan Hippenstiel*
*) Department of Internal Medicine/Infectious Diseases, Charité – Universitätsmedizin
Berlin, 13353 Berlin, Germany (E-mail: Bernd.Schmeck@charite.de); +) Institute for
Medical Microbiology, Justus-Liebig University of Giessen, 35392 Giessen, Germany; #)
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-
Ludwig-Universitat Freiburg, 79104 Freiburg, Germany.
Infection of endothelial cells by Listeria monocytogenes is an essential step in the
pathogenesis of listeriosis. Small GTPases of the Rho family act as molecular switches in
signal transduction. We tested the hypothesis that Rho GTPases contribute to the regulation of
cytokine expression in Listeria monocytogenes infection.
L. monocytogenes induced release of distinct CC and CXC, as well as Th1 and Th2 cytokines
and growth factors by endothelial cells whereas non-invasive L. innocua did not induce
cytokine release and activated Rac1 as shown by pulldown assay. Cytokine expression was
reduced byinhibition of RhoA, Rac and Cdc42 (Clostridium difficile toxin B (TcdB)), and
Rac1-inhibitor Nsc23766. Activating Rho proteins by Escherichia coli CNF1 increased
Listeria-dependent cytokine expression. We analyzed regulation of IL-8 expression in more
detail: Listeria-induced IL-8 release was reduced by inhibition of RhoA, Rac1 and Cdc42
(TcdB) or Rac1while blocking of RhoA/B/C by Clostridium limosum C3 fusion toxin or Rho
kinase by Y27632 had no effect. Activation of RhoA, Rac and Cdc42 (CNF1), but not of
RhoA alone (CNF Y), enhanced Listeria-dependent IL-8 release. Next, we analyzed histone
modifications at the gene-promoter of IL-8. Inhibition of RhoA, Rac1 and Cdc42 (TcdB) and
Rac1 (Nsc23766) reduced Listeria-related recruitment of NF-kappaB/p65 and RNA
Polymerase II to the IL-8 promoter, as well as Lys-8-acetylation of histone H4 and Ser-
10/Lys-14-phosphorylation/acetylation of histone H3 at the IL-8 gene promoter in HUVEC.
In conclusion, Rac1 contributed to epigenetic regulation of L. moncytogenes-induced
cytokine expression by human endothelial cells.
Recent papers:
1: Opitz B, Puschel A, Beermann W, Hocke AC, Forster S, Schmeck B, van Laak V,
Chakraborty T, Suttorp N, Hippenstiel S. Listeria monocytogenes Activated p38 MAPK and
Induced IL-8 Secretion in a Nucleotide-Binding Oligomerization Domain 1-Dependent
Manner in Endothelial Cells. J Immunol. 2006 Jan 1;176(1):484-90.
2: Brell B, Hippenstiel S, David I, Pries AR, Habazettl H, Schmeck B, Suttorp N,
Temmesfeld-Wollbruck B.
Adrenomedullin treatment abolishes ileal mucosal hypoperfusion induced by Staphylococcus
aureus alpha-toxin--an intravital microscopic study on an isolated rat ileum. Crit Care Med.
2005 Dec;33(12):2810-016.
3: Krull M, Bockstaller P, Wuppermann FN, Klucken AC, Muhling J, Schmeck B, Seybold J,
Walter C, Maass M, Rosseau S, Hegemann JH, Suttorp N, Hippenstiel S. Mechanisms of
Chlamydophila pneumoniae Mediated GM-CSF Release in Human Bronchial Epithelial Cells.
Am J Respir Cell Mol Biol. 2005 Dec 9; [Epub ahead of print]
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