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-γ, 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-γ 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-γ promoter. Specific inhibition of histone deacetylases by trichostatin A increased Listeria-induced expression of IL-8, but not of IFN-γ, 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.

MAP kinases and the control of nuclear events

“…Although consensus MAPK histone phosphorylation sites have not been described in vivo, MAPKs can activate histone-phosphorylating kinases (Cheung et al, 2000;Zhong et al, 2001). For example, ERK1/2 and p38a, -b can provoke changes in chromatin structure (Li et al, 2001;Illi et al, 2005;Schmeck et al, 2005) most likely owing to the activation of downstream kinases such as MSK1/2 (Saccani et al, 2002;Soloaga et al, 2003;Lee et al, 2006a;Vicent et al, 2006) or RSK2 (Cheung et al, 2000) that phosphorylate the N-terminal tail of histones. A surprising recent finding is that MAPKs bind to specific actively transcribed genes, as documented in yeast (Pokholok et al, 2006), reinforcing the idea that MAPKs participate actively in chromatin remodeling, perhaps explaining the observation that MAPKs such as p38a and ERK1/2 bind cellular DNA as judged by the use of chromatin immunoprecipitation assays in mammalian cells (Simone et al, 2004;Vicent et al, 2006).…”

Helicobacterpylori-induced modification of the histone H3 phosphorylation status in gastric epithelial cells reflects its impact on cell cycle regulation

“…4,5 Another study reported a drastic decrease of global pH3Ser10 upon L. monocytogenes infection. 6 This decrease was attributed to the bacterium's extracellular presence, and mediated by the cytolysin listeriolysin: a global decrease of pH3Ser10 was dependent on membrane binding of listeriolysin but not on its pore-forming activity.…”

Listeria monocytogenesinduces host DNA damage and delays the host cell cycle to promote infection

“…33 Lm modifies host gene expression via 2 virulence factors, LntA and LLO. [20][21][22]34 LLO modulates host transcription from the extracellular milieu and is degraded once Lm escapes the vacuole, being unlikely to modify host histones from the cytoplasm. 20 Our data do not support a crucial role for LLO or any other bacterial secreted proteins acting from the extracellular milieu.…”

“…19 The interplay between Lm and the host cell cycle is understudied. Albeit Lm remains mostly cytosolic, it interferes with histone modifications 20,21 and chromatin-regulatory factors 22 to modulate host gene expression.…”