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Cyclosporine A promotes in vitro migration of human first-trimester trophoblasts via MAPK/ERK1/2-mediated NF-κB and Ca2+/calcineurin/NFAT signaling
- Source :
- Placenta. 34:374-380
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- Introduction As a calcineurin inhibitor in T-cell activation, cyclosporine A (CsA) has provided the pharmacologic foundation for organ transplantation. We have previously demonstrated that CsA promotes trophoblast growth and invasion in vitro . Here, we further investigated the regulation of CsA on trophoblast migration and the intracellular signaling pathways involved. Methods We evaluated the migration of human primary trophoblasts by using transwell migration assay. CsA-mediated induction of nuclear factor-kappa B (NF-κB) was evaluated by cotransfection with luciferase reporter constructs and luciferase activity assays. Results Treatment with CsA-promoted migration of primary trophoblasts and the HTR8 cell line in a dose-dependent manner. CsA also increased NF-κB-transcriptional activity in trophoblasts in time- and dose-dependent manners. Pharmacologically inhibiting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) 1/2 signaling with U0126 attenuated the CsA-induced cell migration and NF-κB activity in trophoblasts. Furthermore, pretreatment with PDTC, a specific NF-κB inhibitor, inhibited the CsA-induced migration of trophoblasts in dose-dependent manners. Although NFAT activation by ionomycin via calcineurin is accompanied by increased transactivation of NF-κB, pretreatment with the NFAT inhibitor did not affect NF-κB-transcriptional activity. Interestingly, ionomycin and CsA synergize to transactivate NF-κB. Ionomycin-inhibited basal migration of trophoblasts, and pretreatment with CsA reversed the ionomycin-inhibited trophoblast migration. However, the NFAT inhibitor increased basal migration, but not CsA-induced migration, of trophoblasts. Conclusion These observations indicate that both the MAPK/ERK/NF-κB pathway and Ca 2+ /calcineurin/NFAT pathways are involved in the CsA-promoted trophoblast migration. Our findings may help expand the clinical applications of this drug in trophoblast disorder.
- Subjects :
- MAPK/ERK pathway
Biology
Cell Line
chemistry.chemical_compound
Transactivation
Cell Movement
Pregnancy
medicine
Humans
Calcium Signaling
Enzyme Inhibitors
Extracellular Signal-Regulated MAP Kinases
reproductive and urinary physiology
NFATC Transcription Factors
Calcineurin
NF-kappa B
Obstetrics and Gynecology
Trophoblast
NFAT
Cell migration
Trophoblasts
Pregnancy Trimester, First
medicine.anatomical_structure
Reproductive Medicine
chemistry
embryonic structures
Ionomycin
Cyclosporine
Cancer research
Female
Mitogen-Activated Protein Kinases
Signal transduction
Signal Transduction
Developmental Biology
Subjects
Details
- ISSN :
- 01434004
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Placenta
- Accession number :
- edsair.doi.dedup.....60c995ec8675899e49f38b8791182192
- Full Text :
- https://doi.org/10.1016/j.placenta.2013.01.009