Glucocorticoids are recognized for their anti-inflammatory properties. However, in pregnancies complicated by asthma, stress, anxiety and depression, placental inflammation persists, even in the presence of increased circulating cortisol. There are thirteen glucocorticoid receptor (GR) isoforms in the placenta, expression of which vary in relation to maternal stress or excess glucocorticoid exposure and fetal sex. We have previously shown that the translational isoform GRα-D1, was sex-specifically increased in placentae from pregnancies complicated by asthma or depression, and in trophoblast cells exposed to inflammatory stimuli and glucocorticoids in vitro. This study aims to further understand how GRα-D1 is regulated by inflammation and glucocorticoids using human term placental explants.
Term placentae were collected from uncomplicated elective caesarean pregnancies. Explants were cultured in the presence and absence of 1μg/mL lipopolysaccharide (LPS) (n=10 female, n=10 male) and 10ng/mL Interleukin (IL)-6 (n=5 female, n=5 male) with or without hydrocortisone (HC; 1μM) for 4 and 24hr. GR protein isoform expression was quantified by western blot and mRNA expression of inflammatory genes by qPCR. Data were compared between groups using one-way ANOVA with Tukey’s post-hoc test with significance considered at p<0.05.
Nuclear GRα-D1 was significantly upregulated in explants treated with LPS and IL-6 alone and LPS/IL-6+HC at 4 hours post-treatment (p <0.0001). This was associated with an increase in IL-6 and TNFα mRNA (p<0.0001). Sex differences in GRα-D1 expression and potential downstream effectors of GRα-D1 including NF-κB and phosphorylated MAPK protein are currently being investigated.
Increased GRα-D1 activity in the presence of inflammation and excess glucocorticoids could be a potential mechanism by which excess cortisol and inflammation co-exist leading to adverse maternal and fetal outcomes.