The Ontogeny of 25-Hydroxyvitamin D3 1α-Hydroxylase Expression in Human Placenta and Decidua

Abstract

In addition to its classical calciotropic effects, the active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is a potent anti-proliferative/immunomodulatory secosteroid. The enzyme that catalyzes the synthesis of 1,25(OH)(2)D(3), 1alpha-hydroxylase (1alpha-OHase), is expressed in many human tissues, highlighting its possible role as an autocrine/paracrine activator of vitamin D. Immunohistochemical and RNA analyses were used to characterize the ontogeny of 1alpha-OHase expression in human placenta and decidua. Protein for 1alpha-OHase was detectable in trophoblast and decidua; the latter being stronger in decidualized stromal cells than macrophages, with no staining of lymphocytes. Quantitative reverse transcriptase-polymerase chain reaction was used to assess changes in mRNA expression for 1alpha-OHase at different gestations: first (mean, 9.1 +/- 1.5 weeks); second (mean, 14 +/- 1.8 weeks), and third trimester (mean, 39.3 +/- 2.5 weeks). 1alpha-OHase expression in decidua was approximately 1000-fold higher in first (95% confidence limits, 611 to 1376) and second (95% confidence limits, 633 to 1623) trimester biopsies when compared with the third trimester (95% confidence limits, 0.36 to 2.81) (both P < 0.001). In placenta, 1alpha-OHase expression was 80-fold higher in the first (range, 42 to 137) and second (range, 30 to 199) trimester when compared with third trimester biopsies (0.6 to 1.6) (both P < 0.001). Similar results were obtained by semiquantitative IHC. Parallel analysis of the receptor for 1,25(OH)(2)D(3) (vitamin D receptor) indicated that, as with 1alpha-OHase, highest levels of expression occurred in first trimester decidua. However, changes in vitamin D receptor mRNA expression across gestation were less pronounced than 1alpha-OHase. These spatiotemporal data emphasize the potential importance of 1alpha-OHase during early fetoplacental life and, in particular, suggest an autocrine/paracrine immunomodulatory function for the enzyme.

Vitamin D and the Regulation of Placental Inflammation

“…It is possible that loss of 1,25(OH) 2 D 3 production in fetal trophoblast will impact on VDR-expressing cells in maternal decidua: ex vivo we have shown that vitamin D metabolites act to suppress cytokine synthesis by decidual uterine NK cells (11). Likewise, given the abundant expression of Cyp27b1 in human decidua (24), it is probable that some immune functions of vitamin D in the placenta are mediated via autocrine synthesis of 1,25(OH) 2 D 3 in the maternal side of the placenta. This could be addressed by mating Cyp27b1 2/2 females with Cyp27b1 +/2 males, although this has the added complication of pregnancy occurring against a completely abnormal maternal vitamin D backdrop.…”

“…In humans, the enzyme is strongly expressed in both maternal decidualized stromal cells and fetal trophoblastic cells, but it is also detectable in decidual macrophages (24). Analysis of Cyp27b1 protein expression in placentas from WT mice indicated background expression of the enzyme in both decidual and trophoblastic cells of the placenta.…”

“…Placental expression of CYP27B1 in humans (24) and Cyp27b1 in mice (14) is induced early in gestation. In humans, the enzyme is strongly expressed in both maternal decidualized stromal cells and fetal trophoblastic cells, but it is also detectable in decidual macrophages (24).…”

Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells

“…The level of 1␣25(OH) 2 D 3 is, thus, critically dependent upon cellular expression of the enzyme, 25-hydroxyvitamin D 3 (25(OH)D 3 ) 1-␣-hydroxylase (1␣OHase) which catalyzes this reaction. 1␣OHase is expressed predominantly in proximal renal tubular cells (11) where it is subject to tight regulation, but is also expressed in cells from extrarenal sites including skin, endothelium, lymphoid organs, and decidua (12)(13)(14). Macrophages constitute one of the primary sources of extrarenal 1␣25(OH) 2 D 3 production by virtue of their ability to up-regulate 1␣OHase expression (15).…”

Vitamin D and Human Pregnancy

“…Significantly, both proteins are more abundant in 1 st and 2 nd trimester tissue. 28,29 The physical proximity of these proteins is consistent with a localized function of vitamin D in the placenta, with 1,25(OH) 2 D synthesized by decidual or trophoblastic cells acting in an autocrine or paracrine fashion 29 . Such a mechanism would be similar to that previously described for the expression of CYP27B1 and VDR within cells from the immune system 15 .…”