title: Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells.
abstract: 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.
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: Mei-Rong
authors.initials: MR
authors.lastname: Du
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Zhou
authors.forename: Feng-Ting
authors.initials: FT
authors.lastname: Yan
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Zhu
authors.forename: Yin-Yan
authors.initials: YY
authors.lastname: He
authors.forename: Jin-Ying
authors.initials: JY
authors.lastname: Yang
authors.forename: Da-Jin
authors.initials: DJ
authors.lastname: Li
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D064211:Connectin; D016572:Cyclosporine / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009124:Muscle Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014327:Trophoblasts / Q000187:drug effects* / Q000201:enzymology
chemical_list: D064211:Connectin; D007166:Immunosuppressive Agents; D009124:Muscle Proteins; C577285:TTN protein, human; D016572:Cyclosporine; D011494:Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases