title: The granulocyte colony-stimulating factor (G-CSF) upregulates metalloproteinase-2 and VEGF through PI3K/Akt and Erk1/2 activation in human trophoblast Swan 71 cells.
abstract: BACKGROUND
  Although the expression of the granulocyte colony-stimulating factor (G-CSF) and its receptor (G-CSFR) in placental tissues suggests that the cytokine could play a role in placental development, the relevance of G-CSF:G-CSFR interaction in trophoblast cells remains to be studied. Thus, the possible functional role of G-CSF was examined in a human trophoblast cell line (Swan 71 cells).
  
  
  RESULTS
  The expression of G-CSFR was detected by immunocytochemistry and Western blot assays. G-CSF treatment exerted neither a proliferative nor a protective effect on H2O2-mediated cell death in trophoblast cells. Gelatin zymography of supernatants collected from G-CSF-treated cells showed an increment of metalloproteinase-2 (MMP-2) activity. We also found higher MMP-2 and VEGF expression levels in conditioned medium from cells exposed to G-CSF. In addition, it was demonstrated that G-CSF induced the activation of PI3K/Akt and Erk1/2 pathways, which in turn activated NF-kB. By using selective pharmacological inhibitors, it was showed that these pathways are mediating the biological effects produced by G-CSF in Swan 71 cells.
  
  
  CONCLUSIONS
  We have demonstrated for the first time that G-CSF increases MMP-2 activity and VEGF secretion in Swan 71 cells through activation of PI3K/Akt and Erk signaling pathways, both contributing to the translocation of NF-kB to the nucleus. These data suggest that G-CSF is involved in the regulation of trophoblast function, and should be considered as a locally produced cytokine probably contributing to embryo implantation and the development of a functional placenta.
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA- CONICET), Facultad de Farmacia y Bioquímica, Junín 956, Universidad de Buenos Aires, C1113AAD Buenos Aires, Argentina.
authors.forename: V A
authors.initials: VA
authors.lastname: Furmento
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA- CONICET), Facultad de Farmacia y Bioquímica, Junín 956, Universidad de Buenos Aires, C1113AAD Buenos Aires, Argentina.
authors.forename: J
authors.initials: J
authors.lastname: Marino
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA- CONICET), Facultad de Farmacia y Bioquímica, Junín 956, Universidad de Buenos Aires, C1113AAD Buenos Aires, Argentina.
authors.forename: V C
authors.initials: VC
authors.lastname: Blank
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA- CONICET), Facultad de Farmacia y Bioquímica, Junín 956, Universidad de Buenos Aires, C1113AAD Buenos Aires, Argentina. Electronic address: rvroguin@qb.ffyb.uba.ar.
authors.forename: L P
authors.initials: LP
authors.lastname: Roguin
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Cell signaling; Granulocyte colony-stimulating factor; Metalloproteinase; Trophoblast cells; Vascular endothelial growth factor