Glucocorticoids derived from the mother and acting via the placenta are essential for fetal development. However, pregnancy complications that result in excess glucocorticoid exposure can be detrimental to the fetus. The glucocorticoid-regulated mechanisms that confer different outcomes for the fetus may be due to different patterns of placental glucocorticoid receptor (GR) isoform expression and our team discovered that there are multiple placental GR protein isoforms which are conserved across species and vary in relation to sex, fetal growth and maternal complications.
Some GR isoform patterns appear protective against an adverse outcome for the fetus while others appear detrimental including GRα-D1. Placental GRα-D1 expression is increased in the presence of several pregnancy complications and linked to enhanced transcription of pro-inflammatory cytokines. Specifically, GRα-D1 was increased in placentae of women with a mental illness, women with asthma and pregnancies complicated with a small-for gestational age fetus. Furthermore, the increased expression of GRα-D1 was associated with increased expression of inflammatory cytokines and transcription factors in the placentae of complicated pregnancies. Using trophoblast cells in vitro nuclear localisation of GRα-D1 was increased following an inflammatory challenge and its expression was not altered significantly by concomitant hydrocortisone treatment. Placental TNFα, IL-6 and ICAM 1 mRNA were upregulated when GRα-D1 was localised to the nucleus and were not significantly altered in the presence of hydrocortisone. These findings show for the first time that a placental pro-inflammatory response cannot be inhibited by glucocorticoids when GRα-D1 is expressed. We propose this is a new mechanism that may explain why inflammation persists in the presence of high concentrations of glucocorticoids and stress.