The involvement of the progesterone receptor in PIBF and Gal‐1 expression in the mouse endometrium

Abstract

Problem The progesterone‐regulated genes, PIBF and Gal‐1, are key players in the feto‐maternal immunological interaction. This study aims to investigate the expression of PIBF and Gal‐1 in WT and progesterone receptor KO models as well as subsequent effects of PIBF on decidualization of stromal cells. Method of the study PRAKO, PRBKO and PRKO BALB/c mice were used for assessing the role of PR isoforms in PIBF induction. PIBF‐ and Gal‐1 mRNA expression in the uterus was tested by real‐time PCR. The effect of PIBF on decidualization of endometrial stromal cells was verified by anti‐desmin immunofluorescence. Immunohistochemistry was used for testing PIBF expression in the uterus. Gal‐1, ERα and PR positive decidual NK cells were detected by immunofluorescence. Results PIBF mRNA was significantly increased in progesterone‐treated WT mice, but not in PRKO and PRAKO mice. PIBF protein expression was reduced in the endometria of PRKO and PRAKO, but not in PRBKO mice. During a 6‐day culture, PIBF induced decidual transformation of endometrial stromal cells. PIBF expression in the mouse uterus was highest during the implantation window, while Gal‐1 mRNA expression continuously increased between day 2.5 and day 11.5 of gestation. Decidual NK cells express Gal‐1 and ERα, but not PR at day 7.5 murine pregnancy. Conclusion PIBF produced via engagement of PRA, is highly expressed in the endometrium during the implantation window, and plays a role in decidualization. The concerted action of PIBF and Gal‐1 might contribute to the low cytotoxic activity of decidual NK cells.

Steroids, Pregnancy and Fetal Development

“…Overall, the presence of PR in immune cells is a matter of controversy. Although a direct effect of progesterone on e.g., T cells during pregnancy has long been proposed (36)(37)(38)(39), recent findings based on RT-qPCR approaches aiming to detect PR on distinct immune cell subsets failed to confirm the expression of PR in e.g., T and NK cells (9,20,40,41). Promiscuous binding of PR by glucocorticoids has been reported, although there is no consensus on the reported relative binding affinities compared to progesterone (14,15).…”

“…Uterine and placental expression of the PR promotes the local expression of immunomodulatory molecules, such as progesterone-induced blocking factor (PIBF), galectin-1 (Gal-1) (41, 83), and heme oxygenase 1 (Hmox1) (68). These potent immunomodulators are critical for the establishment and continuation of pregnancy, as shown in mouse models and human pregnancies (41,68,83,85,86). For example, PIBF can enhance the synthesis of Th2 cytokines and dampens NK cell cytotoxicity (41) whereas Gal-1 induces a tolerogenic phenotype in dendritic cells, which results in Treg expansion (81).…”

“…These potent immunomodulators are critical for the establishment and continuation of pregnancy, as shown in mouse models and human pregnancies (41,68,83,85,86). For example, PIBF can enhance the synthesis of Th2 cytokines and dampens NK cell cytotoxicity (41) whereas Gal-1 induces a tolerogenic phenotype in dendritic cells, which results in Treg expansion (81). In turn, the enzyme Hmox1 supports the generation of CD8 + CD122 + regulatory T cells that during pregnancy promote placental vascularization and fetal growth (68).…”

Altered Immune Response and Implantation Failure in Progesterone-Induced Blocking Factor-Deficient Mice

“…The progesterone-induced blocking factor (PIBF) is a progesterone-induced mediator which conveys some of the immunological effects of progesterone. The Pibf1 gene contains a progesterone response element (12), which is activated following the engagement of PRA in the mouse uterus (13).…”

“…The latter is due to the fact that PIBF induces an increased synthesis of Th2 cytokines both in vitro (17) and in vivo (18). Recent data show that PIBF plays a role in implantation in mice (13).…”