ERα-dependent stimulation of Lcn2 in uterine epithelium during mouse early pregnancy.

Maintenance of a suitable uterine milieu is important for embryo development and subsequent implantation during early pregnancy. High estrogen level in proestrous and estrous stages is essential for uterine anti-bacterial activity during preimplantation period. Lipocalin-2 is an essential molecule which prevents bacterial infection by sequestering iron. In this study, the highest expression of lipocalin-2 is observed in the endometrial epithelium on day 1 of normal pregnancy and pseudopregnancy, which exhibit a similar hormone scenario. By injecting the agonists for estrogen receptor alpha and estrogen receptor beta in ovariectomized mice, we found estrogen receptor alpha is the dominant member for estrogen regulation on lipocalin-2 expression. Estrogen treatment in estrogen receptor alpha-knockout mice further confirmed the role of estrogen receptor alpha. Using published data from whole-genome estrogen receptor alpha binding site assay, significant estrogen receptor alpha recruitment peaks are found at the downstream of lipocalin-2 gene after estrogen treatment. Furthermore, to study the anti-bacterial activity of lipocalin-2 in uterus, Escherichia coli is injected to mimic bacterial infection. Our results showed an obvious induction of lipocalin-2 in Escherichia coli-treated group. Taken together, this study indicates estrogen regulation of lipocalin-2 in uterine epithelium is mediated by estrogen receptor alpha, and lipocalin-2 may have anti-bacterial activity during early pregnancy.