Pregnancy

Cyclosporin A Promotes Growth and Invasiveness In Vitro of Human First-Trimester Trophoblast Cells Via MAPK3/MAPK1-Mediated AP1 and Ca²⁺/Calcineurin/NFAT Signalling Pathways

Abstract
Cyclosporin A, CsA, has provided the pharmacologic foundation for organ transplantation as a calcineurin inhibitor blocking T cell activation. We have demonstrated that CsA promoted trophoblast viability/proliferation and invasion in vitro. In the present study, we further investigated the intracellular signalling pathways involved in enhancing cell viability/proliferation and invasiveness of human trophoblast induced by CsA. We showed that blocking MAPK3/MAPK1 signaling by U0126 attenuated CsA-increased cell viability and invasiveness of trophoblasts. CsA inhibited ionomycin-stimulated NFAT transactivation in JAR cells, and reversed the ionomycin-inhibited trophoblast invasiveness. However, either activating calcineurin by ionomycin, resulting in NFAT transactivation or inhibiting NFAT by using a NFAT inhibitor had no effect on trophoblast cell viability/proliferation and apoptosis in vitro. Hence, the CsA-induced promotion of trophoblast growth & invasion occurred by overlapping but independent pathways. The MAPK3/MAPK1 pathway was essential for both trophoblast growth and invasion, whereas the Ca²⁺/calcineurin/NFAT pathway was only involved in the CsA-promoted trophoblast invasiveness. Finally, potential crosstalk between MAPK3/MAPK1 and Ca²⁺/calcineurin/NFAT, and its relationship to AP1 activation was investigated. Our findings explored possible signal transduction pathways modulated by CsA, which may lead to the expansion of the clinical applications of this drug.

Key words: Placenta • Signal transduction • Trophoblast • Cyclosporine