Endocrine Abstracts (2004) 7 OC3

Decidual activation of vitamin D3 - a novel immunomodulatory mechanism in early gestation

KN Evans1, BA Innes2, JN Bulmer2, MD Kilby3 & M Hewison1

1Division of Medicine, University of Birmingham, UK; 2Royal Victoria Infirmary, Newcastle-Upon-Tyne, UK; 3Birmingham Womens Hospital, Birmingham, UK.

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3) is a potent antiproliferative/immunomodulatory steroid hormone with many applications outside calcium homeostasis. This is particularly true in the placenta which can generate 1,25D3 locally via the enzyme 1alpha-hydroxylase (CYP27b) in both trophoblast and decidua. We have investigated the potential function of 1,25D3 across gestation using human tissue obtained after local ethical approval. Using real-time RT-PCR we showed that mRNA for CYP27b was greatest in 1st trimester with a 75-fold increase in placenta (P<0.001) and 564-fold increase in decidua (P<0.001) compared to 3rd trimester placenta. The vitamin D receptor (VDR) followed a similar pattern with a 30-fold increase in 1st trimester decidua compared to 3rd trimester placenta (P<0.001). CYP24, encoding the inactivating enzyme 24-hydroxylase was ubiquitous throughout gestation, indicating increased 1,25D3 signalling in early gestation. Using positive immunomagnetic selection we purified stromal (CD10positive) and immune-enriched (CD10negative) decidual cells and demonstrated expression of CYP27b, VDR and CYP24 mRNA in both fractions. In 1st trimester CD10postitive cells CYP27b was 326 times higher than similar 3rd trimester cells (P<0.001). CYP27b was also expressed 158 times higher in 1st trimester compared to 3rd trimester CD10negative cells (P<0.001). This, in conjunction with our finding that CYP27b expression only correlated with the macrophage marker CD14 in CD10negative cells (not stromal cells), highlights a potential immunomodulatory role for 1,25D3 in early gestation. To investigate this further we cultured whole decidual cell suspensions in the presence of 1,25D3 (100nM) for 12-18 hours and then used immunomagnetic selection to isolate CD56postitive natural killer (NK) cells from 1st trimester decidua. Cells cultured in 1,25D3 showed reduction of NK activity as measured by lysis of K562 cells in a standard chromium release assay. These data provide evidence for an immunomodulatory role for vitamin D in early gestation via localised synthesis of active 1,25D3.

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