Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells
Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells
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环孢菌素 A 通过 MAPK/ERK 信号传导诱导肌联蛋白表达，并提高人滋养层细胞的增殖和侵袭潜力
DOI：
10.1093/humrep/dem222
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发表时间：
2007-09-01
影响因子：
6.1
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
背景技术背景：环孢菌素A（CsA）是一种强有力的免疫抑制剂，已被广泛用于预防器官排斥反应和治疗某些自身免疫性疾病。我们前期的研究表明，低浓度CsA可促进人早孕滋养细胞的增殖和侵袭，并抑制其凋亡。本研究进一步探讨了其可能的作用机制和信号通路。方法：用CsA处理人早孕滋养层细胞后，通过抑制性消减杂交（SSH）筛选差异表达基因，并通过逆转录-聚合酶链反应（RT-PCR）和Western blot对人早孕滋养层细胞中的差异表达基因titin进行鉴定。酶联免疫吸附试验（ELISA）检测丝裂原活化蛋白激酶（MAPK）活性。研究结果：CsA可剂量依赖性地刺激滋养细胞增殖和侵袭，并与titin的转录呈正相关，提示CsA通过诱导titin的表达来调节滋养细胞的生物学功能。此外，CsA处理增加了MAPK活性，并且通过丝裂原活化蛋白MAPK（MEK）抑制剂U 0126阻断信号通路，抑制CsA诱导的滋养细胞titin转录。结论：我们的研究结果表明，titin的表达诱导CsA通过激活MAPK途径，这可能参与促进人类滋养层细胞的生长和侵袭，这是有益的胚胎存活。
BACKGROUND: Cyclosporin A (CsA) is a powerful immunosuppressive that has been widely used to prevent organ rejection and to treat certain autoimmune diseases. Our previous study showed that CsA at low concentrations could promote proliferation and invasion, and inhibit apoptosis, of human first trimester trophoblasts. In the present study, we further explored the potential mechanism and signal pathway. METHODS: After treatment of JAR cells with CsA, we screened the differentially expressed genes by suppression subtractive hybridization (SSH), and characterized the differentially expressed gene, titin, in human first-trimester trophoblasts by reverse transcription -polymerase chain reaction and Western blot. Mitogen-activated protein kinase (MAPK) activity was evaluated by ELISA. RESULTS: CsA stimulated proliferation and invasion of human trophoblasts in a dose-dependent manner, and this appeared to be positive correlated with titin transcription, suggesting that CsA regulates biological functions of human trophoblast by inducing titin expression. Furthermore, the CsA treatment increased the MAPK activity, and blocking of the signaling pathway by Mitogen-activated protein MAPK (MEK) inhibitor, U0126, inhibited CsA-induced titin transcription in trophoblasts. CONCLUSIONS: Our results indicate that titin expression is induced by CsA via activation of MAPK pathways and this may possibly be involved in promoting human trophoblast growth and invasiveness, which is beneficial to embryo viability.