Histone deacetylase inhibition by trichostatin A mitigates LPS induced TNFα and IL-10 production in human placental explants

Abstract

IntroductionCytokine expression by the placenta is known to change across pregnancy, and is altered in a number of pathologies; however the precise mechanisms of cytokine regulation in gestational tissues are not well understood. It has been previously reported that cytokine protein production in gestational tissues is regulated in a tissue-specific manner and appears to be epigenetically regulated. MethodsIn this study we investigated changes in cytokine mRNA expression and protein production by term placental explants maintained at 8% O2 in the presence or absence of lipopolysaccharide (LPS) (5 μg/mL) and the histone deacetylase inhibitor trichostatin A (TSA) (300 nM). ResultsAs expected, exposure to LPS stimulated gene expression and protein production of the proinflammatory cytokines IL-1β, IL-6, IL-8 and TNFα, as well as the anti-inflammatory cytokine IL-10. While TSA alone had little effect, TSA co-treatment mitigated the effects of LPS on TNFα and IL-10 protein production with an accompanying reduction in TNFα mRNA transcript levels detected. However, TSA had no significant effect on LPS induced IL-1β, IL-1ra, IL-6 or IL-8 mRNA expression or protein production. DiscussionThe data from this study show that TSA selectively mitigates the stimulatory effect of LPS on TNFα mRNA expression, TNFα protein production and IL-10 protein production. As there is no compensatory effect on IL-1β, IL-1ra, IL-6, or IL-8 mRNA expression or protein production, this results in a dysregulation of the cytokine balance. ConclusionsInsights into HDAC regulation of cytokine expression may provide novel therapeutic strategies for conditions associated with dysregulation of the cytokine network, such as preeclampsia and infection mediated preterm labor.