title: IFN-gamma-mediated extravillous trophoblast outgrowth inhibition in first trimester explant culture: a role for insulin-like growth factors.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynaecology, University of British Columbia, 2H30-4500 Oak Street, Vancouver, BC, Canada.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Hu
authors.forename: Rusung
authors.initials: R
authors.lastname: Tan
authors.forename: Colin D
authors.initials: CD
authors.lastname: MacCalman
authors.forename: Genevieve
authors.initials: G
authors.lastname: Eastabrook
authors.forename: Se-Hyung
authors.initials: SH
authors.lastname: Park
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dutz
authors.forename: Peter
authors.initials: P
authors.lastname: von Dadelszen
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D013002:Somatomedins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D016023:Integrins; D017527:Receptor, IGF Type 2; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D007371:Interferon-gamma; D017526:Receptor, IGF Type 1