Glucocorticoids regulate natural killer cell function epigenetically

Abstract

Although glucocorticoids are well known for their capacity to suppress the immune response, glucocorticoids can also promote immune responsiveness. It was the purpose of this investigation to evaluate the molecular basis for this apparent dichotomous immunologic effect. Glucocorticoid treatment of natural killer cells (NK) was shown to reduce NK cell cytolytic activity by reduction of histone promoter acetylation for perforin and granzyme B, which corresponded with reduced mRNA and protein for each. In contrast, glucocorticoid treatment increased histone acetylation at regulatory regions for interferon gamma and IL-6, as well as chromatin accessibility for each. This increase in histone acetylation was associated with increased proinflammatory cytokine mRNA and protein production upon cellular stimulation. These immunologic effects were evident at the level of the individual cell and demonstrate glucocorticoids to epigenetically reduce NK cell cytolytic activity while at the same time to prime NK cells for proinflammatory cytokine production.

Aging and peripheral lipopolysaccharide can modulate epigenetic regulators and decrease IL-1β promoter DNA methylation in microglia

“…As epigenetic regulation of other pro-inflammatory genes such as TNF-α and IL-6 have been demonstrated in other immune cell types such as natural killer cells and peripheral monocytes/macrophages (Eddy, et al, 2014, Sullivan, et al, 2007), it will be pertinent to explore regulation by DNA methylation and other epigenetic modifications in microglia, as well as other signature genes relevant to aging such as those recently found in the microglial sensome (Hickman, et al, 2013) or other recent transcriptomic studies (Holtman, et al, 2015, Orre, et al, 2014). …”

Innate Immune System at the Maternal–Fetal Interface: Mechanisms of Disease and Targets of Therapy in Pregnancy Syndromes

“…119 Several authors demonstrated that GCs epigenetically reduce NK cytolytic activity, while at the same time prime NK cells for proinflammatory cytokine production. 120 Thus, relationship between steroid treatment and innate immune regulation is still under investigation (Table I, Fig. 2).…”

Prenatal Dexamethasone and Postnatal High-Fat Diet Decrease Interferon Gamma Production through an Age-Dependent Histone Modification in Male Sprague-Dawley Rats

“…GC treatment was also shown to enhance activity of histone deacetylases (HDACs) 7, 9, 10, and 11 of mice splenic memory T cells [41]. However, a recent study showed that chronic GC treatment of natural killer cells (NK) can reduce NK cell granzyme B productions by reduction of histone promoter H4K8Ac as well as H3K9Ac while increasing IFN-γ and IL-6 production by increasing H4K8Ac/H3K27Ac as well as H3K4me3 in regulatory regions at the same time [42]. This dichotomous effect of GC on immune function seems to be dose- and time-dependent [42].…”

“…However, a recent study showed that chronic GC treatment of natural killer cells (NK) can reduce NK cell granzyme B productions by reduction of histone promoter H4K8Ac as well as H3K9Ac while increasing IFN-γ and IL-6 production by increasing H4K8Ac/H3K27Ac as well as H3K4me3 in regulatory regions at the same time [42]. This dichotomous effect of GC on immune function seems to be dose- and time-dependent [42]. Thus deacetylation cannot totally explain the effects of GC treatment on histone modification.…”

“…Age-associated changes in DNA methylation have been well documented; however, information regarding site-specific histone modification with age is still limited [47,48]. Kawakami et al reported that H3 Lys9 acetylation decreased and H3 Ser10 phosphorylation increased with age in rat livers [42]; however, their study lacked functional validation. In the current study, we explored the IFN-γ production ability of rat splenocytes at newborn, young adult, and middle-age stages.…”