title: 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.
abstract: 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.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, People's Republic of China.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Zhou
authors.forename: Mei-Rong
authors.initials: MR
authors.lastname: Du
authors.forename: Lin
authors.initials: L
authors.lastname: Dong
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Zhu
authors.forename: Jin-Ying
authors.initials: JY
authors.lastname: Yang
authors.forename: Ying-Yan
authors.initials: YY
authors.lastname: He
authors.forename: Da-Jin
authors.initials: DJ
authors.lastname: Li
mesh_terms: D016572:Cyclosporine / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012333:RNA, Messenger / Q000378:metabolism; D014327:Trophoblasts / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D016572:Cyclosporine; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9