Hum. Reprod. Advance Access published online on June 12, 2007
Human Reproduction, doi:10.1093/humrep/dem097
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Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via MAPK pathway
1 Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, People's Republic of China 2 Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan 430071, People's Republic of China 3 Department of Obstetrics and Gynecology, The Affiliated Hospital, Hainan Medical College, Haikou 570102, People's Republic of China
4 Correspondence address. Tel/Fax: +86-21-63457331; E-mail: djli{at}shmu.edu.cn
BACKGROUND: Cyclosporin A (CsA) is an immunosuppressant for preventing from allograft rejection. Little is known, however, about the effect of CsA on the materno–fetal relationship.
OBJECTIVE: To probe into effect of CsA on the invasiveness of human first-trimester trophoblast cells, explore possible molecules involved, and provide 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 using an invasion assay, and the transcription, translation and proteolytic activity of MMP 9 and MMP 2 in these cells were determined 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 significantly promoted the invasiveness of the first-trimester human trophoblast cells. The transcription, translation and proteolytic activity of MMP 9 and MMP 2 by theses cells also increased after treatment with CsA. U0126, a MEK inhibitor, remarkably inhibited the enhanced invasiveness and activity of MMP 9 and MMP 2 of first-trimester human trophoblast 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.
Key words: cyclosporin A/invasiveness/MAPK/matrix metalloproteinase/trophoblast cell
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