Leukemia Inhibitory Factor Induces Proopiomelanocortin via CRH/CRHR Pathway in Mouse Trophoblast.

He Wang,Toshihisa Hatta,Hiroko Masuta,Hiroki Shimada,Daisuke Sakai,Hiroki Shoji,Hiromi Sakata-Haga,Tsuyoshi Tsukada,Mitsuhiro Tomosugi

doi:10.3389/fcell.2021.618947

Abstract

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 Pomc via CRH upregulation in mouse trophoblast. In vivo, protein levels of LIF and CRH peak in mouse placenta at 13.5 days post coitum. In mouse placenta, Crh 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 Pomc induced by LIF in mouse trophoblast stem cells in vitro. After LIF supplementation for 3 days, we found that the increased expression of Crh-induced by new supplementation of LIF was earlier than that of Pomc. Furthermore, LIF-induced upregulation of Pomc 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 Pomc expression through the CRH/CRHR1 pathway, and placental ACTH secretion is induced directly by LIF via the JAK/STAT3 pathway.

Highlights

The placenta is essential to mammalian pregnancy, with many roles that go beyond fetal nutrition, including both endocrine and immune functions (Coe and Lubach, 2014)
We found that protein levels of corticotropin-releasing hormone (CRH) and Leukemia inhibitory factor (LIF) were higher at 13.5 dpc compared with that found at 15.5 and 17.5 dpc (Figures 1A,B), and CRH and LIF protein levels decreased following placental development
CRH and LIF receptor (LIFR) were widely expressed in the decidua, trophoblast giant cells, and syncytiotrophoblast layer of mouse placenta, in the syncytiotrophoblast cells at 13.5 dpc (Figure 1C)

Summary

Introduction

The placenta is essential to mammalian pregnancy, with many roles that go beyond fetal nutrition, including both endocrine and immune functions (Coe and Lubach, 2014). Our previous study on rodents showed that maternal LIF induces proopiomelanocortin (POMC) expression and placental secretion of adrenocorticotropic hormone (ACTH), which stimulates fetal nucleated red blood cells to release LIF, and enhance neuron production in the ventricular zone of fetal cerebral neocortex (Simamura et al, 2010, 2015). It was reported that placental CRH exerts a local paracrine action on the production of Pomc and secretion of ACTH from the placenta (Petraglia et al, 1987; Margioris et al, 1988). Based on these findings, we hypothesized that this LIF/CRH pathway is involved in LIF-induced expression of placental Pomc and secretion of placental ACTH. We examined whether LIF indirectly acts via CRH/CRHR to stimulate Pomc expression and ACTH secretion from mouse trophoblast in vitro and in vivo

Methods

Results

Conclusion