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Early Placental Insulin-Like Protein (INSL4 or EPIL) in Placental and Fetal Membrane Growth¹

Department of Obstetrics and Gynecology,³ John A. Burns School of Medicine, Pacific Biosciences Research Center,⁴ University of Hawaii, Honolulu, Hawaii 96822 Department of Biochemistry and Molecular Biology,⁵ Medical University of South Carolina, Charleston, South Carolina 29425

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.

apoptosis, early placental insulin-like peptide, growth restriction, placenta

² Correspondence: Lynnae Millar, Department of Obstetrics and Gynecology and Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, 1960 East West Rd., Biomed T-510, Honolulu, HI 96822. FAX: 808 956 5361; mill8lynn{at}aol.com