Vitamin D facilitates trophoblast invasion through induction of epithelial-mesenchymal transition.

PROBLEM: Vitamin D deficiency increases the risk of developing pregnancy-related complications, including preeclampsia and small-for-gestational-age infants. Vitamin D was demonstrated to promote the invasiveness of human extravillous trophoblasts (EVTs). However, whether vitamin D induces the epithelial-mesenchymal transition (EMT) of EVTs remains unclear. Therefore, we investigated whether vitamin D promotes EMT and the related signaling pathways. METHOD OF STUDY: In this study, we performed EMT experiments using JAR cells based on the expression of the mesenchymal markers and vitamin D receptor. JAR cells were treated with calcitriol, the active form of vitamin D. Western blotting was performed to evaluate EMT markers and key molecules of signaling pathways. Invasion assays were conducted. Expression and secretion of MMPs were analyzed by real-time PCR and zymography. RESULTS: Calcitriol significantly enhanced EMT and the invasive capability of JAR cells, along with increased expression and secretion of MMP-2 and MMP-9. Moreover, ERK signaling pathway was activated by calcitriol. The effects of calcitriol were neutralized by ERK signaling blocker. CONCLUSION: Calcitriol facilitated EMT induction and expression of MMPs via ERK signaling pathway, which promoted the invasive capability of EVTs. Further studies are warranted to elucidate the potential application of vitamin D in the prevention of pregnancy complications.

Activation of NOD-1/JNK/IL-8 signal axis in decidual stromal cells facilitates trophoblast invasion.

Decidual stromal cells (DSCs) are known to regulate trophoblast invasion via unveiled mechanism yet. And nucleotide-binding oligomerization domain-containing protein 1 (NOD1) may influence on this DSC-trophoblast interaction. We investigated the mechanism underlying the DSC-mediated regulation of trophoblast invasion and the effect of NOD1 on their cross talk. Using human primary DSCs, BeWo cell invasion was measured. Cytokine secretion and MAP kinase signaling were examined in DSCs following treatment with NOD1 agonist, Tri-DAP. DSCs secreted IL-8 and increased trophoblast invasion. Tri-DAP further increased IL-8 secretion from DSCs via JNK pathway and facilitated both MMP-2 production and trophoblast invasion compared with control. Upon cotreatment of IL-8 and anti-IL-8 antibody to BeWo cells, the number of invading trophoblasts and MMP-2 production decreased significantly. These results suggest that IL-8 from DSCs may play a role to increase the invasiveness of trophoblast cells into the decidua via NOD1/JNK pathway.