Role Of Progesterone In Regulation Research Articles

Progesterone Promotes Differentiation of Human Cord Blood Fetal T Cells into T Regulatory Cells but Suppresses Their Differentiation into Th17 Cells

Progesterone, a key female sex hormone with pleiotropic functions in maintenance of pregnancy, has profound effects on regulation of immune responses. We report in this work a novel function of progesterone in regulation of naive cord blood (CB) fetal T cell differentiation into key T regulatory cell (Treg) subsets. Progesterone drives allogeneic activation-induced differentiation of CB naive, but not adult peripheral blood, T cells into immune-suppressive Tregs, many of which express FoxP3. Compared with those induced in the absence of progesterone, the FoxP3(+) T cells induced in the presence of progesterone highly expressed memory T cell markers. In this regard, the Treg compartment in progesterone-rich CB is enriched with memory-type FoxP3(+) T cells. Moreover, CB APCs were more efficient than their peripheral blood counterparts in inducing FoxP3(+) T cells. Another related function of progesterone that we discovered was to suppress the differentiation of CB CD4(+) T cells into inflammation-associated Th17 cells. Progesterone enhanced activation of STAT5 in response to IL-2, whereas it decreased STAT3 activation in response to IL-6, which is in line with the selective activity of progesterone in generation of Tregs versus Th17 cells. Additionally, progesterone has a suppressive function on the expression of the IL-6 receptor by T cells. The results identified a novel role of progesterone in regulation of fetal T cell differentiation for promotion of immune tolerance.

Multidrug Resistance Phosphoglycoprotein (ABCB1) in the Mouse Placenta: Fetal Protection1

The multidrug resistance phosphoglycoprotein ATP-binding cassette subfamily B (ABCB1) actively extrudes a range of structurally and functionally diverse xenobiotics as well as glucocorticoids. ABCB1 is present in many cancer cell types as well as in normal tissues. Although it has been localized within the mouse placenta, virtually nothing is known about its regulation. In the mouse, two genes, Abcb1a and Abcb1b, encode ABCB1. We hypothesized that there are changes in placental Abcb1a and Abcb1b gene expression and ABCB1 protein levels during pregnancy. Using in situ hybridization, we demonstrated that Abcb1b mRNA is the predominant placental isoform and that there are profound gestational changes in the expression of both Abcb1a and Abcb1b mRNA. Placentas from pregnant mice were analyzed between Embryonic Days (E) 9.5 and 19 (term approximately 19.5d). Abcb1b mRNA was detected in invading trophoblast cells by E9.5, peaked within the placental labyrinth at E12.5, and then progressively decreased toward term (P < 0.0001). Abcb1a mRNA, although lower than that of Abcb1b at midgestation, paralleled changes in Abcb1b mRNA. Changes in Abcb1 mRNA were reflected by a significant decrease in ABCB1 protein (P < 0.05). A strong correlation existed between placental Abcb1b mRNA and maternal progesterone concentrations, indicating a potential role of progesterone in regulation of placental Abcb1b mRNA. In conclusion, there are dramatic decreases in Abcb1a and Abcb1b mRNA and in ABCB1 at the maternal-fetal interface over the second half of gestation, suggesting that the fetus may become increasingly susceptible to the influences of xenobiotics and natural steroids in the maternal circulation.

Up-regulation and nuclear localization of beta-catenin in endometrial carcinoma in response to progesterone therapy.

Ovarian hormones are considered to be capable of regulating expression of beta-catenins. A possible role of beta-catenin in alteration of cell morphology has been proposed, but little is known about beta-catenin expression during changes in the tumor morphology of endometrial carcinomas induced by progesterone therapy. To clarify changes in expression of beta-catenin and their relation to morphological alteration, expression of hormone receptors and several cell kinetic markers, sequential biopsy and hysterectomy specimens of 23 endometrial carcinoma and 6 complex hyperplasia with atypia (atypical hyperplasia) cases receiving progesterone therapy were investigated. In vitro assay was also conducted using two endometrial carcinoma cell lines (HEC265 and Ishikawa) expressing progesterone receptors (PRs). An increase of nuclear beta-catenin accumulation was evident during progesterone therapy in endometrial carcinomas and atypical hyperplasias. The nuclear labeling indices were significantly associated with gene mutations and alteration in morphological features in response to progesterone, independently of the status of Ki-67, p21WAF1 and p27Kip1, and hormone receptors. In HEC265 having a beta-catenin gene mutation (A32V), cytoplasmic beta-catenin levels were elevated by progesterone treatment, linked to down-regulation of PR expression, but such changes were relatively minor in Ishikawa without the gene alterations. These findings demonstrate a possible role of progesterone in regulation of beta-catenin expression in endometrial tumors. Moreover, nuclear beta-catenin accumulation, like gene abnormalities, is associated with the alteration of tumor morphology due to progesterone, indicating that beta-catenin may be a clinically useful marker of hormone therapeutic effects.

Regulation of uterine immune function by progesterone—lessons from the sheep

Survival of the fetal allograft results from orchestrated adjustments in activity of maternal lymphoid cells as well as in trophoblast gene expression. One molecule that regulates uterine immune responsiveness is progesterone. In fact, uterine skin graft survival and susceptibility to bacterial infections are increased by progesterone. This review focuses on the role of progesterone in regulation of uterine immune function in the sheep. While the importance of progesterone as a regulator of immune function likely varies between species, concepts derived from the sheep model may prove pertinent to other species also. The actions of progesterone on uterine immune function in the ewe change during pregnancy. Before day 50 of gestation, i.e. when the uterus is still dependent upon the corpus luteum as a source of progesterone, concentrations of progesterone are probably not high enough at the maternal–fetal interface to inhibit lymphocyte activation. During this early period of pregnancy, progesterone inhibits uterine immune function by inducing endometrial secretion of a protein called uterine milk protein (UTMP) that itself is inhibitory to lymphocyte function. After day 50 of pregnancy, it is likely that the placenta produces sufficient amounts of progesterone to directly inhibit lymphocyte proliferation. Additional inhibition is achieved because of sustained synthesis of UTMP. Accordingly, progesterone acts to regulate uterine immune function in ways that allows for inhibition of immune responses at the utero–placental interface without systemic immunosuppression.

Role of progesterone in regulating uteroovarian venous concentrations of PGF 2 α and PGE 2 during the estrous cycle and early pregnancy in ewes

The role of progesterone in regulation of uteroovarian venous concentrations of prostaglandins F 2 α (PGF 2α) and E 2 (PGE 2) during days 13 to 16 of the ovine estrous cycle or early pregancy was examined. At estrus, ewes were either mated to a fertile ram or unmated. On day 12 postesturus, ewes were laparotomized and a catheter was inserted into a uteroovarian vein. Six mated and 7 unmated ewes received no further treatment. Fifteen mated and 13 unmated ewes were ovariectomized on day 12 and of these, 7 mated and 5 unmated ewes were given 10 mg progesteron sc and an intravaginal pessary containing 30 mg of progesterone. Uteroovarian venous samples were collected every 15 min for 3 h on days 13 to 16 postestrus. Mating resulted in higher mean daily concentrations of PGE 2 in the uterovarian vein than in unmated ewes. Ovariectomy prevented the rise in PGE 2 with day in mated ewes but had no effect in unmated ewes. Progesterone treatment restored PGE 2 in ovariectomized, mated ewes with intact embros. Mating had no effect on mean daily concentrations of PGF 2α or the patterns of the natural logarithm (ln) of the invariance of PGF 2α. Ovariectomy resulted in higher mean concentrations and ln invariances of PGF 2α on day 13 and lower mean concentrations and ln invariances of PGF 2α on days 15 and 16. Replacement with progesterone prevented these changes in patters of mean concentrations and ln variances of PGF 2α following ovariectomy. It is concluded that progesterone regulates the release of PGF 2α from the uterus, maintaining high concentrations while also preventing the occurrence of the final peaks of PGF 2α which are seen with falling concentrations of progesterone. This occurs in both pregnant and non-pregnant ewes. Progesterone is also needed to maintain increasing concentrations of PGE 2 in mated ewes.