Wang He, Sakata-Haga Hiromi, Masuta Hiroko, Tomosugi Mitsuhiro, Tsukada Tsuyoshi, Shimada Hiroki, Sakai Daisuke, Shoji Hiroki, Hatta Toshihisa
Department of Anatomy, Kanazawa Medical University, Uchinada, Japan.
Department of Obstetrics, The First Hospital of China Medical University, Shenyang, China.
Front Cell Dev Biol. 2021 Jul 19;9:618947. doi: 10.3389/fcell.2021.618947. eCollection 2021.
We previously showed that maternal leukemia inhibitory factor (LIF) induces placental production of adrenocorticotropic hormone (ACTH), which stimulates fetal nucleated red blood cells to further secrete LIF and promote neurogenesis in rodent brains. However, the underlying mechanism of LIF-dependent ACTH induction remains unclear. Recently, we found that LIF induces corticotropin-releasing hormone (CRH) in mouse trophoblast stem cells. This finding supports the results of a previous study that CRH, which is produced by the placenta, induces placental ACTH production. In this study, we examined whether the effects of LIF are mediated by the induction of via CRH upregulation in mouse trophoblast. , protein levels of LIF and CRH peak in mouse placenta at 13.5 days post coitum. In mouse placenta, mRNA and protein levels significantly increased 3 h after intraperitoneal injection of LIF (5 μg/kg body weight) into dams at 13.5 days post coitum. We also examined the effect of LIF-induced CRH on the expression of induced by LIF in mouse trophoblast stem cells . After LIF supplementation for 3 days, we found that the increased expression of -induced by new supplementation of LIF was earlier than that of . Furthermore, LIF-induced upregulation of in mouse trophoblast stem cells was attenuated by inhibition of the CRH/CRHR1 pathway, whereas LIF-induced secretion of ACTH was attenuated by inhibition of the JAK/STAT3 pathway. Therefore, LIF indirectly increases placental expression through the CRH/CRHR1 pathway, and placental ACTH secretion is induced directly by LIF via the JAK/STAT3 pathway.
我们之前的研究表明，母体白血病抑制因子（LIF）可诱导胎盘产生促肾上腺皮质激素（ACTH），后者刺激胎儿有核红细胞进一步分泌LIF，并促进啮齿动物大脑中的神经发生。然而，LIF依赖性ACTH诱导的潜在机制仍不清楚。最近，我们发现LIF可在小鼠滋养层干细胞中诱导促肾上腺皮质激素释放激素（CRH）。这一发现支持了先前的一项研究结果，即由胎盘产生的CRH可诱导胎盘ACTH的产生。在本研究中，我们检测了LIF的作用是否通过上调小鼠滋养层细胞中的CRH介导。LIF和CRH的蛋白水平在小鼠妊娠13.5天时在胎盘中达到峰值。在小鼠妊娠13.5天时，向母鼠腹腔注射LIF（5μg/kg体重）3小时后，小鼠胎盘中CRH的mRNA和蛋白水平显著升高。我们还检测了LIF诱导的CRH对LIF在小鼠滋养层干细胞中诱导的ACTH表达的影响。补充LIF 3天后，我们发现新补充LIF诱导的ACTH表达增加早于CRH。此外，在小鼠滋养层干细胞中，抑制CRH/CRHR1途径可减弱LIF诱导的ACTH上调，而抑制JAK/STAT3途径可减弱LIF诱导的ACTH分泌。因此，LIF通过CRH/CRHR1途径间接增加胎盘ACTH表达，而胎盘ACTH分泌则由LIF通过JAK/STAT3途径直接诱导。
