The Role of Histone Deacetylases in Cytokine Regulation in Human Gestational Tissues

Abstract

Normal pregnancy results in significant immunologic alterations, including the maintenance of a heightened inflammatory state, controlled through the appropriate balance of pro and anti-inflammatory cytokines. Several pathologies of pregnancy such as pre-eclampsia, intrauterine growth restriction and preterm birth have been associated with variations in cytokine expression, both from the placenta and gestational membranes, and in the maternal circulation. Following their investigation as anticancer drugs, histone deacetylase inhibitors were identified as having anti-inflammatory actions, leading to further studies into how histone deacetylases may be involved in cytokine regulation. However, despite the importance of appropriate histone deacetylase activity during development little is known about histone deacetylases (HDACs) in the placenta and membranes. The overall aim of this research was to investigate the role of histone deacetylases in cytokine regulation in human gestational tissues. HDAC expression was characterised in term placental, amnion and choriodecidual tissues obtained after elective caesarean section. All eighteen human HDACs were expressed, with tissue-specific differences in expression and production identified. A time course was then established to examine the potential links between HDAC activity and cytokine expression and production by placental villous explants in vitro. Term explants were maintained at a physiologically relevant oxygen tension with/without an inflammatory stimulus and/or histone deacetylase inhibitor. In the presence of an inflammatory stimulus, HDAC inhibition resulted in mitigation of the normal response, with reduced production of both the proinflammatory cytokine tumour necrosis factor α (TNFα) and the anti-inflammatory cytokine interleukin-10 (IL-10) and accompanying reductions in TNFα expression. Despite this, levels of other cytokines were not affected, resulting in dysregulated cytokine expression and suggesting that HDAC activity is essential to appropriate cytokine expression. Furthermore both reduced HDAC activity and inflammatory stimulus resulted in selective feedback on HDAC expression and production. These data support a role for HDAC as regulators of cytokine production. Several pathological conditions of pregnancy are already associated with dysregulation of the cytokine network. Modulation of HDAC activity or histone acetylation levels may represent an underlying cause/ consequence of cytokine dysregulation in these conditions, as well as a potential therapeutic strategy.