Evidence for Epigenetic Regulation of Pro-Inflammatory Cytokines, Interleukin-12 and Interferon Gamma, in Peripheral Blood Mononuclear Cells from PTSD Patients

Abstract

While Post Traumatic Stress Disorder (PTSD) is associated with immune dysfunction, the underlying mechanisms remain unclear. Studies suggest a role for involvement of epigenetic mechanisms and microRNAs (miRNAs). Here, we examined genome-wide histone and DNA methylation in the peripheral blood mononuclear cells (PBMCs) in PTSD. We noted significant differences in histone H3 trimethylation at K4, K9, K27 and K36 sites in PTSD when compared to control. While overall DNA methylation level did not differ significantly between control and PTSD, the promoters of several individual genes (e.g., Interferon gamma (IFNG) and Interleukin (IL)-12B) were differentially methylated. ChIP-seq data revealed that the promoter of IFNG and TBX-21 was associated with the activation marker H3K4me3 in PTSD. The transcript levels of both IFNG and TBX-21 were higher in PTSD correlating well with the altered methylation patterns. Furthermore, PTSD patients showed increased expression of IL-12 in their PBMCs. Analysis of both histone and DNA methylation markers suggested that the expression of IL-12 was also possibly activated through epigenetic modification. Knockdown of lysine (K)-specific demethylase 5B (KDM5B), or inhibition of DNA (Cytosine-5-)-methyltransferase 1 (DNMT1) caused up-regulation of IL-12. Furthermore, the expression of these cytokines was also regulated by miRNAs. Our miRNA microarray identified many down regulated miRNAs in PTSD that are predicted to target IFNG and IL-12. Consequently, we showed that up-regulation of hsa-miR-193a-5p could decrease the expression of IL-12. Overall, the current study demonstrated that the elevated expression of pro-inflammatory cytokines in PTSD patients might be regulated by multiple epigenetic mechanisms and miRNAs.

White matter integrity alterations in post‐traumatic stress disorder

“…While regular cortisol production serves a protective function against excessive inflammation (Silverman, Pearce, Biron, & Miller, 2005), exposure to excessive stress or trauma can result in dysregulated HPA axis function (Charmandari, Tsigos, & Chrousos, 2005;Elenkov, Iezzoni, Daly, Harris, & Chrousos, 2005). A recent study has found evidence suggesting epigenetic mechanisms of the histone and DNA methylation regulation of genes involved in proinflammatory cytokine expression is upregulated in PTSD subjects compared to controls (Bam et al, 2016). Epigenetic mechanisms have also been linked to brainderived neurotrophic factor (BDNF) expression involved in the extinction of conditioned fear (Blouin, Sillivan, Joseph, & Miller, 2016;Bredy et al, 2007).…”

World Trade Center (WTC) dust exposure in mice is associated with inflammation, oxidative stress and epigenetic changes in the lung

“…Increases in H3K4 have been reported in humans after prolonged exposure to metal components of particulate matter air pollution (Cantone et al, 2011). While early increases in H3K4 methylation 3 d after exposure to WTC dust are likely linked to acute inflammation, decreases at 21 d are consistent with chronic inflammation (Bam et al, 2016). COX-2 gene expression has been reported to be regulated, in part, by chromatin modifications (Cao et al, 2007).…”

Hydroxytyrosol supplementation modulates the expression of miRNAs in rodents and in humans

“…Among the six selected miRNAs from mice studies, miR193a-5p was found to be induced by HT consumption in humans. In PBMCs, it was showed very recently that up-regulation of miR-193a-5p could have antiinflammatory effects by decreasing the expression of IL-12 [51].…”