Cyclosporin A promotes growth and invasiveness in vitro of human first-trimester trophoblast cells via MAPK3/MAPK1-mediated AP1 and Ca2+/calcineurin/NFAT signaling pathways
Cyclosporin A promotes growth and invasiveness in vitro of human first-trimester trophoblast cells via MAPK3/MAPK1-mediated AP1 and Ca2+/calcineurin/NFAT signaling pathways
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环孢素 A 通过 MAPK3/MAPK1 介导的 AP1 和 Ca2/钙调神经磷酸酶/NFAT 信号通路促进人妊娠早期滋养层细胞的体外生长和侵袭
DOI：
10.1095/biolreprod.107.063503
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发表时间：
2008-06-01
影响因子：
3.6
通讯作者：
Li, Da-Jin
中科院分区：
文献类型：
--
作者：
Du, Mei-Rong;Zhou, Wen-Hui;Li, Da-Jin
环孢菌素A(CsA)作为一种钙调神经磷酸酶抑制剂，阻断T细胞活化，为器官移植提供了药理学基础。我们已经证明CsA在体外可以促进滋养层细胞的存活、增殖和侵袭。在本研究中，我们进一步研究了细胞内信号转导通路在增强CsA诱导的人滋养层细胞活性/增殖和侵袭力方面的作用。我们发现，用U0126阻断丝裂原活化蛋白激酶3(MAPK3)/MAPK1信号通路可减弱CsA诱导的滋养层细胞活力和侵袭力。环孢菌素A可抑制离子霉素刺激的JAR细胞活化T细胞核因子(NFAT)的反式激活，并逆转离子霉素抑制的滋养层细胞侵袭力。然而，无论是用离子霉素激活钙调神经磷酸酶，导致NFAT反式激活，还是用NFAT抑制剂抑制NFAT，在体外对滋养层细胞的存活、增殖和凋亡都没有影响。因此，CsA诱导的滋养层细胞生长和侵袭的促进是通过重叠但独立的途径发生的。MAPK3/MAPK1通路对滋养层细胞的生长和侵袭都是必不可少的，而钙/钙调神经磷酸酶/NFAT通路仅参与CsA促进的滋养层细胞侵袭性。最后，研究了MAPK3/MAPK1和钙/钙调神经磷酸酶/NFAT之间的潜在串扰及其与激活蛋白1激活的关系。我们的发现探索了CsA可能调节的信号转导途径，这可能导致该药物临床应用的扩大。
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 crosstalk 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.