Molecular inhibition of histone deacetylation results in major enhancement of the production of IL-1β in response to LPS

Abstract

It has been postulated that the progression of human pregnancy to term is, in part, the result of a relative maternal Th 2 immunological state. This can be activated in some cell types by modifying DNA methylation and histone acetylation status. We demonstrate that the molecular inhibition of histone deacetylation, using trichostatin A (TSA), in human choriodecidual explants leads to a massive increase in lipopolysaccharide (LPS)-stimulated IL-1␤. The inhibition of histone deacetylation had no effect on LPS-stimulated TNF-␣ production or production of the other cytokines studied (IL-10, IL-1 receptor antagonist). The molecular inhibition of DNA methylation and histone deacetylation, using 5-aza-2Ј-deoxycytidine and TSA, respectively, in human choriodecidual explants also results in an increase in the basal production of TNF-␣ but not that of IL-1␤. The differential response is unique, and the relative uncoupling of IL-1␤ and TNF-␣ responsiveness may have importance in other biological systems and provide new therapeutic targets for pathologies where upregulation of IL-1␤ is known to be a causative factor. interleukin-1␤; lipopolysaccharide; histane deacetylation; human pregnancy CYTOKINES ARE KEY INFLAMMATORY MEDIATORS that regulate numerous cellular responses (20). They can be categorized as proinflammatory (e.g., IL-1␤ and TNF-␣) or anti-inflammatory [e.g., IL-10 and IL-1 receptor antagonist (IL-1Ra)] depending on the cellular response initiated. Cytokines can further be categorized as Th 1 or Th 2 on the basis of whether they initiate a cellular or antibody-generating immune response, respectively (18). Maintenance of a Th 2 type phenotype is critical to the maintenance of pregnancy (11,17,34). Recent studies have demonstrated that alterations of DNA methylation in T cells can lead to an adaption to a Th 2 type phenotype (14).Prostaglandin H synthase (PGHS)-2 is a key biosynthetic enzyme of arachidonic acid metabolism. Recent reports have demonstrated that PGHS-2 activity is suppressed in cancer cell lines by aberrantly enhanced DNA methylation and reduced histone acetylation; activity can be restored by treatment with inhibitors of DNA methylation and histone deacetylation (12,32). Enhanced intrauterine prostaglandin production is requisite for the onset and progression of labor at term and preterm, and the most extremely preterm deliveries are mainly a result of an intrauterine infection associated with increased cytokine production (24). Recently, we (16) have demonstrated that prostaglandin production by intrauterine tissues of women at term of pregnancy can be regulated by inhibition of DNA methylation and histone deacetylation. Hence, we hypothesize that the regulation of DNA methylation and histone acetylation in key genes in human gestational tissues may be critical for the initiation of labor and delivery both at term and preterm.To evaluate this proposition, we have now determined the effects of inhibiting DNA methylation and histone deacetylation on cytokine production by human choriodecidua, which...

Epigenetic Differences in Cortical Neurons from a Pair of Monozygotic Twins Discordant for Alzheimer's Disease

“…However, more recent data indicates no difference in methylation of the APP gene in AD [9]. Furthermore, inducible nitric oxide synthase, interleukin 1, and tumor necrosis factor-α are all increased as part of the inflammatory response in AD cortex [10]; all their respective genes are methylated; and all show enhanced secretion with hypomethylation [11], [12], [13]. At the protein level, protein phosphatase 2A is methylated (probably by peptidylarginine methyltransferases or lysine methyltransferases), and its hypomethylation results in tau hyperphosphorylation [14].…”

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

“…24 TSA was also reported to suppress cell proliferation and epithelial-mesenchymal transition through inactivation of the component of LPS/TLR4 signaling pathway, such as phosphatidylinositol-3-kinase (PI3K)/Akt, p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase(ERK)1/2 pathways. 25,26 Meanwhile, Sato et al 27 reported that inhibition of HDACs with TSA in human choriodecidual explants led to a massive increase in LPS-stimulated interleukin (IL)-1β, indicating that HDACs can also negatively regulate the expression of some target genes. In our present study, by means of TLR4-siRNA- lentivirus infection, we further demonstrated that LPS stimulated the expression and activation of HDAC-4, -5, and -7 through TLR4, implying that the TLR4-mediated expression and activation of HDACs may play an important role in LPSinduced epigenetic regulation of gene expression in lung fibroblasts and phenotype transition.…”

Inflammatory and steroid receptor gene methylation in the human amnion and decidua

“…DNA (CpG) methylation has been proposed to participate in this process (Mitchell 2006, Sato & Mitchell 2006, Wang et al 2008, Menon et al 2012, Mitchell et al 2012, because this epigenetic chromatin modification is involved in establishing, maintaining and altering gene expression patterns during development.…”