The Expression And Function Of Lcn2 In Mouse Uterus During Early Pregnancy

Embryo implantation is the interaction beteween blastocysts and receptive uterus, which plays a crucial role in establishing pregnancy. The embryo and uterus are dependent and coordinated. The endometrial stomal cells undergo proliferation and differentiation since the embryos invade the endometrium and this progress is called decidualization. Lipocalin-2(Lcn2) is a secretory protein which is related to some pathological processes such as inflammation, infection and tumor metastasis, and can transport some lipophilic molecules such as leukotriene and platelet activating factors. Lcn2 is strongly expressed in endometrial epithelial cells during proestrus, estrous and days 1~2 of early pregnancy. This study was to investigate the expression, regulation and function of Lcn2 during peri-implantation period in mouse uterus.In situ hybridization was used to examine Lcn2 m RNA location in the uterus of early pregnancy, pseudopregnancy, delayed and activated implantation, artificial decidualization. The results showed that a strong Lcn2 m RNA level was detected in endometrial epithelial cells during pregnancy of days 1~2. Lcn2 m RNA was weakened in day 3 of pregnancy and no Lcn2 m RNA was detected in day 4 of pregnancy. The expression pattern of Lcn2 in pseudopregnancy is similar to that of early pregnancy. Estrogen strongly induced Lcn2 expression in a time-dependent manner, which was not seen in ER?ko mice. Escherichia coli and staphylococcus aureus can also stimulate Lcn2 expression after intraluminally infused into uterine horns on day 4 of pseudopregnancy. In addition, Lcn2 m RNA level was abundant in uterus after LPS stimulated the ovariectomized mice.PGs are important for both implantation and decidualization. Lcn2 is expressed in the stromal cells around the embryo on day 5 of pregnancy, and no Lcn2 m RNA signal was detected in inter-implantation site. Lcn2 m RNA localization at day 5 was similar to that of m PGES-1. Lcn2 recombinant protein induced m PGES1 expression in stromal cells. However, when Lcn2 was knocked down by si RNA, m PGES1 m RNA level is declined in stromal cells. m PGES-1 is a rate-limiting enzyme for PGE2 production. Lcn2 may regulate m PGES1 expression during the period of implantation to insure PGE2 production. The process is beneficial to vasular permeability and implantation.P4 can increase Lcn2 level in stromal cells, which was blocked by RU486. To further study the mechanism of P4 induction on Lcn2 expression, promoter analysis on Lcn2 was performed. A c-Myc binding site was found in the promoter zone. Both Akt and c-Myc inhibitors can suppress Lcn2 expression, and P4 cannot induce Lcn2 expression in the presence of Akt and c-Myc inhibitors. Our results indicate that Akt-c-Myc pathway involves in the progesterone regulation on Lcn2.