Millar Lynnae, Streiner Nicole, Webster Lisa, Yamamoto Sandra, Okabe Rachel, Kawamata Tasha, Shimoda Jacqueline, Büllesbach Erika, Schwabe Christian, Bryant-Greenwood Gillian
Department of Obstetrics and Gynecology, University of Hawaii, Honolulu, 96822, USA.
Biol Reprod. 2005 Oct;73(4):695-702. doi: 10.1095/biolreprod.105.039859. Epub 2005 Jun 15.
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.
早期胎盘胰岛素样蛋白（INSL4或EPIL）是胰岛素超家族激素的成员，在胎盘中高度表达。我们已在足月时证实了这一点，并表明它由母体蜕膜表达。尽管孕期子宫内会产生大量局部作用的生长因子，但我们推测INSL4在胎儿和胎盘生长中起重要作用。我们用细胞系和原代细胞证明，它通过引起细胞凋亡和细胞活力丧失具有生长抑制作用。我们使用原代羊膜上皮细胞进行流式细胞术检测，结果显示INSL4可导致细胞凋亡，50 ng/ml时呈剂量相关且具有显著性（P < 0.05）。通过检测培养基中的核基质蛋白证实了这一点。相比之下，松弛素处理（高达200 ng/ml）对细胞凋亡无影响。添加INSL4（3 - 30 ng/ml）也会导致细胞活力丧失，尽管它对细胞周期不同阶段的细胞数量没有影响。胎盘凋亡在正常胎盘发育和胎儿生长受限过程中都是一个重要过程。因此研究了生长不一致的异卵双胞胎中的体内临床相关性。与正常生长的同胞相比，生长受限双胞胎胎盘中INSL4基因的表达增加了一倍，这表明它可能与更高水平的细胞凋亡和细胞活力丧失有关，因此可能导致胎儿生长受限。
