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Mol. Hum. Reprod. Advance Access originally published online on April 22, 2008
Molecular Human Reproduction 2008 14(5):281-289; doi:10.1093/molehr/gan018
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

IFN-{gamma}-mediated extravillous trophoblast outgrowth inhibition in first trimester explant culture: a role for insulin-like growth factors

Yuxiang Hu1,2, Rusung Tan2,3, Colin D. MacCalman1,2, Genevieve Eastabrook1,2, Se-Hyung Park1,2, Jan P. Dutz2,4 and Peter von Dadelszen1,2,5

1Department of Obstetrics and Gynaecology, University of British Columbia, 2H30-4500 Oak Street, Vancouver, BC, Canada V6H 3N1 2Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada 3Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada 4Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada

5 Correspondence address. E-mail: pvd{at}cw.bc.ca

Pre-eclampsia is often associated with inadequate cytotrophoblast invasion and remodelling of the uterine spiral arteries. Examining a first trimester, 2D in vitro explant culture model which mimics in vivo placentation, including trophoblast column formation and extravillous cytotrophoblast (EVT) migration, we previously suggested that excessive maternal decidual natural killer cell interferon (IFN-{gamma}) limits EVT migration. Types-1 and -2 insulin-like growth factor (IGF-1, IGF-2) are trophic for EVT, act through their surface receptors, IGFR-1 and IGFR-2, and are regulated by the IGF-binding proteins (IGFBPs). Could the observed IFN-{gamma}-mediated inhibition of EVT outgrowth and migration be related to either expression changes of IGF-1 or IGF-2, their receptors, their binding proteins, or apoptosis? Using the 2D explant culture model, we examined the effect of IFN-{gamma} exposure on IGF-1 and -2, IGFR-1 and -2, IGFBPs and apoptosis. IFN-{gamma} relatively increased IGF-1 and -2 secretion. In EVT, IFN-{gamma} decreased IGFR-2, but not IGFR-1 expression. IGBP-2, -3 and -4 production were not influenced by IFN-{gamma}. IFN-{gamma} induced trophoblast apoptosis measured by the highly sensitive M30 neo-epitope, but not caspase 3 activity, in conditioned medium and EVT cell lysates. The observed IFN-{gamma}-mediated EVT migration inhibition may occur through the down-regulation of IGFR-2 and subtle induction of EVT apoptosis.

Key words: villous explant culture/IFN-{gamma}/insulin-like growth factors/insulin-like growth factor receptors/insulin-like growth factor binding proteins

Submitted on August 30, 2007; resubmitted on March 11, 2008; accepted on April 9, 2008.


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