Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via the mitogen-activated protein kinase pathway
Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via the mitogen-activated protein kinase pathway
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环孢素 A 通过丝裂原激活蛋白激酶途径增加基质金属蛋白酶 9 和 2 的表达以及妊娠早期人滋养层细胞的体外侵袭力
DOI：
10.1093/humrep/dem097
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发表时间：
2007-10-01
影响因子：
6.1
通讯作者：
Li, Da-Jin
中科院分区：
文献类型：
--
作者：
Zhou, Wen-Hui;Du, Mei-Rong;Li, Da-Jin
研究背景：环孢素A（CsA）是一种免疫抑制剂，用于预防同种异体移植排斥反应。然而，关于CsA对母胎关系的影响知之甚少。本研究旨在探讨环孢素A（CsA）对人早孕滋养层细胞侵袭力的影响及其可能的分子机制，以期为妊娠并发症滋养层细胞功能紊乱提供新的治疗途径。研究方法：采用Matrigel侵袭实验检测CsA对人早孕滋养细胞侵袭能力的影响，采用RT-PCR、in-cell Western和酶谱法检测细胞内基质金属蛋白酶（MMP- 9）和MMP-2的转录、翻译和蛋白水解活性。用细胞内蛋白质印迹法检测CsA诱导的滋养细胞细胞外信号相关激酶（ERK）1/2磷酸化水平。结果如下：环孢素A增加人早孕滋养细胞的侵袭指数（P < 0.01），以及mRNA、蛋白水平（P均< 0.01）和蛋白水解活性MMP-9和MMP-U 0126（一种丝裂原活化蛋白/细胞外信号调节激酶（MEK）抑制剂）的作用（P < 0.05），抑制CsA诱导的细胞侵袭力增强和MMP-9、MMP-2活性的升高。CsA对ERK 1/2的激活具有时间依赖性。结论：CsA通过激活丝裂原活化蛋白激酶/细胞外信号相关激酶（ERK）1/2信号通路，提高人早孕滋养层细胞的侵袭力和MMP 9、MMP 2的活性，提示CsA对人早孕滋养层细胞的功能具有良好的调节作用。
Background: Cyclosporin A (CsA) is an immunosuppressent which is used for preventing allograft rejection. Little is known, however, about the effect of CsA on the materno-fetal relationship. Our aim was to probe into the effect of CsA on the invasiveness of human first- trimester trophoblast cells and explore possible molecules involved, with a view to providing a new therapeutic approach for pregnancy complications with trophoblast disorder. Methods: The effects of CsA on invasion of the first-trimester human trophoblasts were examined by matrigel invasion assay, and the transcription, translation and proteolytic activity of matrix metalloproteinase (MMP- 9) and MMP-2 in these cells were estimated by RT-PCR, in-cell Western and zymography, respectively. The phosphorylation level of extracellular-signal related kinase (ERK) 1/2 in trophoblasts induced by CsA was also evaluated by in- cell Western. Results: CsA increased the invasive index of first- trimester human trophoblasts (P < 0.01), as well as the messenger RNA, protein levels (both P < 0.01) and proteolytic activity (P < 0.05) of MMP-9 and MMP-U0126, a mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor, inhibited the enhanced invasiveness and activity of MMP-9 and MMP-in these cells induced by CsA. In addition, CsA activated the ERK1/2 in a time-dependent manner. Conclusions: CsA improves the invasiveness and activity of MMP 9 and MMP 2 in vitro of the first-trimester human trophoblast cells through activation of mitogen-activated protein kinase/extracellular-signal related kinase (ERK) 1/2 signaling pathway, which suggests this drug has a favorable modulation on the function of human first-trimester trophoblast cells.