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Cyclosporin A Promotes Growth and Invasiveness In Vitro of Human First-Trimester Trophoblast Cells Via MAPK3/MAPK1-Mediated AP1 and Ca²⁺/Calcineurin/NFAT Signaling Pathways¹

Laboratory for Reproductive Immunology,³ Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Department of Obstetrics and Gynecology,⁴ The Affiliated Hospital, Hainan Medical College, Haikou 570102, China

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 the human trophoblast induced by CsA. We showed that blocking mitogen-activated protein kinase 3 (MAPK3)/MAPK1 signaling by U0126 attenuated CsA-increased cell viability and invasiveness of trophoblasts. Cyclosprin A inhibited ionomycin-stimulated nuclear factor of activated T-cells (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 using an NFAT inhibitor had no effect on trophoblast cell viability/proliferation and apoptosis in vitro. Hence, the CsA-induced promotion of trophoblast growth and 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 cross-talk between MAPK3/MAPK1 and Ca²⁺/calcineurin/NFAT and its relationship to activator protein 1 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.

cyclosporine, placenta, signal transduction, trophoblast

¹Supported by National Basic Research Program of China 2006CB944009 to D.J.L., Key Project of National Natural Science Foundation of China 30730087 to D.J.L., National Natural Science Foundation of China 30670787 to D.J.L., Foundation for Younger Investigator of Chinese Education Ministry 20070246037 to M.R.D., Natural Science Foundation of Shanghai 06ZR14120 to M.R.D., Shanghai Leading Academic Discipline Project B117 to D.J.L., and Program for Outstanding Medical Academic Leader to D.J.L.

Correspondence: ²Da-Jin Li, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China. FAX: 0086 21 63457331; e-mail: djli{at}shmu.edu.cn

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