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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

Authors :
Ch. Sun
Q. Fu
Y. Tao
Ch.-L. Tang
R. Zhu
H.-L. Piao
S.-C. Wang
D.-J. Li
Meirong Du
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.

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