Glucocorticoid-induced apoptosis in human decidua: a novel role for 11 beta-hydroxysteroid dehydrogenase in late gestation
JCY Chan1, KN Evans2, B Innes3, JN Bulmer3, PM Stewart2, M Hewison2 & MD Kilby1
Author affiliations
1Division of Reproduction and Child Health, Birmingham Women's Hospital, University of Birmingham, Birmingham, UK; 2Division of Medical Sciences, Institute of Biomedical Research, Medical School, University of Birmingham, Birmingham, UK; 3School of Clinical and Laboratory Sciences (Pathology), University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
Glucocorticoids (GCs) play a fundamental role in the endocrinology of pregnancy but excess GC in utero may lead to IUGR. Protection against fetal exposure to GCs is provided by the enzyme 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) located in the placental trophoblast. By contrast, relatively little is known concerning the function of GC-activating 11beta-HSD1 which is expressed within maternal decidua. We have used human deciduas (n=32 first, n=10 second and n=9 third trimester elective caesarean sections) to assess: i) changes in 11beta-HSD1 with gestation using human decidual cells; ii) a role for GC within the decidua. Tissue was used for preparation of RNA and decidual cell cultures including purified cell populations. Expression of mRNA for 11beta-HSD1 increased in second (9.3-fold, p<0.01) and third (210-fold, p<0.001) trimesters. In partially-purified third trimester decidual cells, expression of 11beta-HSD1 increased in both CD10 negative (non-stromal) (185-fold, p<0.001) and CD10 positive (stromal) (11-fold) cell fractions. The ontogeny of 11beta-HSD1 was paralleled by increased expression of the NADPH-generating enzyme, hexose-6-phosphate dehydrogenase (H6PDH) in both CD10 negative (40-fold, p<0.01) and CD10 positive (5.5-fold) cell fractions, which resulted in a switch to predominant 11beta-HSD1 reductase activity and higher levels of cortisol generation in the third trimester. Functional studies indicated that 11beta-HSD1-mediated cortisol production was associated with increased decidual apoptosis. Caspase 3 expression was higher in third trimester decidua, particularly in CD10 negative non-stromal cells (20.4-fold higher than first trimester, p<0.01). Flow cytometric analyses of annexin V and propridium iodide revealed increased apoptosis in primary cultures of third trimester decidual cells when treated with cortisol, cortisone or dexamethasone (100 nM) for 24 hours. Cortisone-induced apoptosis was blocked by glycyrrhetinic acid, an inhibitor of 11beta-HSD. We therefore propose that GC-induced programmed cell death in decidua is an important mechanism for the maintenance of normal fetoplacental development.