title: Cyclosporin A promotes proliferating cell nuclear antigen expression and migration of human cytotrophoblast cells via the mitgen-activated protein kinase-3/1-mediated nuclear factor-κB signaling pathways.
abstract: Our previous studies have demonstrated that cyclosporin A (CsA) promotes the proliferation and migration of human trophoblasts via the mitgen-activated protein kinase-3/1 (MAPK3/1) pathway. In the present study, we further investigated the role of nuclear factor (NF)-κB in the CsA-induced trophoblast proliferating cell nuclear antigen (PCNA) expression and migration, and its relationship to MAPK3/1 signal. Flow cytometry was used to analyze the expression of PCNA in trophoblasts. The migration of human primary trophoblasts was determined by wound-healing assay and transwell migration assay. Western blot analysis was performed to evaluate the activation of NF-κB p65 and NF-κB inhibitory protein I-κB in human trophoblasts. We found that treatment with CsA promotes PCNA expression and migration of human trophoblast in a dose-associated manner. Blocking of the MAPK3/1 signal abrogated the enhanced PCNA expression and migration in trophoblasts by CsA. In addition, CsA increased the phosphorylation of NF-κB p65 and the inhibitor I-κB in human trophoblasts in a time-related manner. Pretreatment with MAPK3/1 inhibitor U0126 abrogated the phosphorylation of NF-κB p65 and I-κB. Accordingly, the CsA-induced enhancement of PCNA expression and migration in trophoblasts was also decreased. This CsA-induced enhancement in the expression and migration of trophoblasts was abolished by pretreatment with pyrrolidine dithiocarbamate, a specific NF-κB inhibitor. Thus, our results suggest that CsA promotes PCNA expression and migration of human trophoblasts via MAPK-mediated NF-κB activation.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College Shanghai 200011, China.
authors.forename: Song-Cun
authors.initials: SC
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Hai-Lan
authors.initials: HL
authors.lastname: Piao
authors.forename: Chuan-Lin
authors.initials: CL
authors.lastname: Tang
authors.forename: Chan
authors.initials: C
authors.lastname: Sun
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.forename: Ming Qing
authors.initials: MQ
authors.lastname: Li
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Jin
authors.forename: Da-Jin
authors.initials: DJ
authors.lastname: Li
authors.forename: Mei-Rong
authors.initials: MR
authors.lastname: Du
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009570:Nitriles; D018809:Proliferating Cell Nuclear Antigen; C113580:U 0126; D016572:Cyclosporine; D048052:Mitogen-Activated Protein Kinase 3
keywords: Cyclosporine A; PCNA; migration; signal transduction pathway; trophoblast