title: Early placental insulin-like protein (INSL4 or EPIL) in placental and fetal membrane growth.
abstract: Early placental insulin-like protein (INSL4 or EPIL) is a member of the insulin superfamily of hormones, which is highly expressed in the placenta. We have confirmed this at term and shown it to be expressed by the maternal decidua. Although an abundance of locally acting growth factors are produced within the uterus during pregnancy, we hypothesized that INSL4 plays an important role in fetal and placental growth. We have demonstrated with cell lines and primary cells that it has a growth-inhibitory effect by causing apoptosis and loss of cell viability. We used primary amniotic epithelial cells for flow cytometry to show that INSL4 caused apoptosis, which was dose-related and significant (P < 0.05) at 50 ng/ml. This was confirmed by measurement of the nuclear matrix protein in the media. In comparison, relaxin treatment (up to 200 ng/ml) had no effect on apoptosis. The addition of INSL4 (3-30 ng/ml) also caused a loss of cell viability, although it had no effect on the numbers of cells at different phases of the cell cycle. Placental apoptosis is an important process in both normal placental development and in fetal growth restriction. Therefore, an in vivo clinical correlate was sought in fraternal twins exhibiting discordant growth. Expression of the INSL4 gene was doubled in the placenta of the growth-restricted twin compared to the normally grown sibling, suggesting that it may be linked to a higher level of apoptosis and loss of cell viability and, therefore, that it may contribute to fetal growth restriction.
authors.affiliation: Department of Obstetrics and Gynecology, University of Hawaii, Honolulu, 96822, USA. mill8lynn@aol.com
authors.forename: Lynnae
authors.initials: L
authors.lastname: Millar
authors.forename: Nicole
authors.initials: N
authors.lastname: Streiner
authors.forename: Lisa
authors.initials: L
authors.lastname: Webster
authors.forename: Sandra
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Rachel
authors.initials: R
authors.lastname: Okabe
authors.forename: Tasha
authors.initials: T
authors.lastname: Kawamata
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Shimoda
authors.forename: Erika
authors.initials: E
authors.lastname: Büllesbach
authors.forename: Christian
authors.initials: C
authors.lastname: Schwabe
authors.forename: Gillian
authors.initials: G
authors.lastname: Bryant-Greenwood
mesh_terms: D000650:Amnion / Q000166:cytology / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D005321:Extraembryonic Membranes / Q000254:growth & development* / Q000378:metabolism*; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000494:pharmacology; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D012016:Reference Values; D012065:Relaxin / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D014427:Twins / Q000235:genetics
chemical_list: C101126:INSL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D012065:Relaxin; D019311:Staurosporine