Progesterone-induced blocking factor (PIBF) influences the expression of membrane progesterone receptors (mPRs) on peripheral CD4+ T lymphocyte cells in normal fertile females (original) (raw)
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Progesterone and the immunology of pregnancy
The Journal of Steroid Biochemistry and Molecular Biology, 2005
The foetal-placental unit is a semi-allograft and the immunological recognition of pregnancy, together with the subsequent response of the maternal immune system, is necessary for a successful pregnancy. This recognition of pregnancy results in an upregulation of progesterone receptors on activated lymphocytes amongst placental cells and decidual CD56+ cells. In the presence of sufficient progesterone, these cells synthesise progesterone induced blocking factor (PIBF), a mediator that exerts substantial anti-abortive activities. PIBF affects B cells and induces an increased production of asymmetric, non-cytotoxic antibodies. It also alters the profile of cytokine secretion by activated lymphocytes resulting in an increase in the production of non-inflammatory, non-cytotoxic interleukins (IL) (e.g. IL-3, IL-4 and IL-10) and a reduction in the production of inflammatory, cytotoxic cytokines (e.g. interferon (IFN)-␦, tumour necrosis factor (TNF)-␣ and IL-2). PIBF also inhibits the cytotoxity of natural killer (NK) cells by blocking their degranulation and perforin release, as well as inhibiting IFN-␦, TNF-␣ and IL-2-mediated transformation of NK cells into detrimental lymphokine activated killer (LAK) cells.
American Journal of Reproductive Immunology, 1996
Zs, Varga P, Szereday L, Kelemen K. The immunological pregnancy protective effect of progesterone is manifested via controlling cytokine production. AJRI 1996; 35:348-351 0 Munksgaard, Copenhagen PROBLEM: This study was aimed at investigating the involvement of an altered cytokine pattern in the immunomodulatory and anti-abortive effects of a progesterone-induced immunomodulatory protein (PIBF). METHOD: PIBF expression on lymphocytes of healthy pregnant women and from women at risk for premature pregnancy termination was determined. In sera of the same women TNFa was quantified by a bioassay using L929 cells. NK activity was determined by a single cell cytotoxicity assay. Cytokine production of the lymphocytes or murine spleen cells was measured by ELISA or detected by immunocytochemistry. In pregnant mice endogenous PIBF activity was neutralized by anti-PIBF IgG. RESULTS: Sera of women at risk for premature pregnancy termination contained significantly higher concentrations of TNFa than those from healthy pregnant women and PIBF expression on the lymphocytes was inversely related to serum concentration of TNFa. Increased NK activity of lymphocytes after neutralization of endogenous PIBF activity is corrected by anti-IL2 treatment and PIBF inhibits IL12 expression on activated lymphocytes. PIBF increases IL-10 production by activated spleen cells. In pregnant mice, neutralization of endogenous PIBF activity by specific antibody results in increased resorption rate and reduced splenic IL-10 production. CONCLUSIONS: Our data allow the assumption that via blocking IL-12 production PIBF inhibits NK activation with a concomitant reduction of TNFa levels. Disturbances in this system might lead to the expression of the known synergistic effect of IL-12 and TNFa, resulting in a Th 1 type cytokine dominance and pregnancy termination.
Progesterone Modulation of Pregnancy-Related Immune Responses
Frontiers in immunology, 2018
Progesterone (P4) is an important steroid hormone for the establishment and maintenance of pregnancy and its functional withdrawal in reproductive tissue is linked with the onset of parturition. However, the effects of P4 on adaptive immune responses are poorly understood. In this study, we took a novel approach by comparing the effects of P4 supplementation longitudinally, with treatment using a P4 antagonist mifepristone (RU486) in mid-trimester pregnancies. Thus, we were able to demonstrate the immune-modulatory functions of P4. We show that, in pregnancy, the immune system is increasingly activated (CD38, CCR6) with greater antigen-specific cytotoxic T cell responses (granzyme B). Simultaneously, pregnancy promotes a tolerant immune environment (IL-10 and regulatory-T cells) that gradually reverses prior to the onset of labor. P4 suppresses and RU486 enhances antigen-specific CD4 and CD8 T cell inflammatory cytokine (IFN-γ) and cytotoxic molecule release (granzyme B). P4 and RU4...
Journal of Reproductive Immunology, 1983
Cytotoxic activity and progesterone binding capacity of the lymphocytes, together with serum progesterone concentrations, were determined in women with normal pregnancy or with a clinical diagnosis of threatened abortion or threatened premature labour. The lymphocytes of women with threatened abortion or threatened premature labour showed significantly higher cytotoxic activity (P < 0.001) and significantly lower progesterone binding capacity (P < 0.001) than did lymphocytes obtained from the healthy pregnant women. Significant inverse correlation was found between progesterone binding capacity and cytotoxic activity of the lymphocytes (P < 0.001), but the progesterone concentration of the pregnancy serum appeared to have no influence on the other two parameters. The findings indicate that intact progesterone binding capacity of the lymphocytes is arf essential factor for the manifestation of the blocking effect exerted by pregnancy serum on lymphocyte 6ytotoxicity in vitro.
Journal of Reproductive Immunology, 2009
Spontaneous miscarriage and preterm delivery are common complications of pregnancy. Pro-inflammatory cytokines have been shown to be associated with recurrent spontaneous miscarriage (RSM) and preterm delivery (PTD) and these have led to exploration of ways to downregulate pro-inflammatory cytokines and/or to upregulate anti-inflammatory cytokines. Progesterone-induced blocking factor (PIBF) is a molecule with inhibitory effects on cell-mediated immune reactions. We have ascertained the effects of PIBF on secretion of selected type 1 and type 2 cytokines by peripheral blood mononuclear cells from healthy non-pregnant women, women undergoing normal pregnancy, women with unexplained RSM and women with PTD. Peripheral blood mononuclear cells from 30 women with a history of unexplained RSM, 18 women undergoing PTD, 11 women with normal pregnancy and 13 non-pregnant healthy women were stimulated with a mitogen in the absence and presence of PIBF after which the levels of cytokines released into culture supernatants were determined by ELISA. Production of the type 2 cytokines IL-4, IL-6 and IL-10 by lymphocytes from the RSM and PTD groups and of IL-4 and IL-10 by lymphocytes from healthy pregnant women was significantly increased upon exposure to PIBF, while the levels of type 1 cytokines were not affected. Ratios of type 1:type 2 cytokines were decreased, suggesting a shift towards Th2 bias. PIBF did not affect cytokine production by lymphocytes from non-pregnant women. Thus, PIBF acts on lymphocytes in pregnancy to induce a type 1 to type 2 cytokine shift by upregulating the production of type 2 cytokines.
Progesterone and Non-specific Immunologic Mechanisms in Pregnancy
American Journal of Reproductive Immunology, 1997
Copen hagen PROBLEM: Progesterone-dependent immunomodulation is one of the mechanisms that enables pregnancy to proceed to term. Immunologic effects of progesterone are mediated by a protein named the progesterone-induced blocking factor (PIBF). Among other effects this protein inhibits natural killer (NK) activity and displays an anti-abortive effect in mice. Recently we have shown that PIBF induces a Th2 shift in vitm. The present study was aimed at investigating the in vivo effect of PIBF on cytokine production, as well as the relationship between cytokine production, NK activity, and pregnancy loss. METHOD O F STUDY: Balb-c mice on day 8.5 of pregnancy were injected intraperitoneally with 0.5 mg of rabbit anti-PIBF immunoglobulin G (IgG). Another group of mice was simultaneously treated with anti-NK monoclonal antibodies. Mice treated with the same amount of normal rabbit serum or untreated mice of similar gestational age were used as controls. The animals were sacrificed on day 10.5, and their uteri were inspected. The ratio of living and resorbed embryos was determined. NK activity as well as cytokine expression on the spleen cells were determined by immunocytochemistry and enzymc-linked immunoadsorbent assay (ELISA). RESULTS: Mitogen-activated spleen cells from anti-PIBF-treated mice produced significantly (P < 0.001) less IL-10 than those o f pregnant control mice. A significantly higher percentage (P < 0.001) of spleen cells from anti-PIBF-treated mice expressed interferon-y (IFNy) as determined by immunocytochemistry, than those of untreated pregnant mice. There was a positive relationship between the percentage of IFNy-positive spleen cells and resorption rates, and an inverse relationship between the latter and interleukin-I0 (IL-10) production. All these effects were corrected by treatment with anti-NK antibodies. CONCLUSION: Our data suggest that PIBF contributes to the success of gestation via cytokine-mediated inhibition of NK activity.
Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy
BJOG : an international journal of obstetrics and gynaecology, 2015
To provide evidence of the existence of membrane progesterone receptor alpha (mPRα) on regulatory T cells (Treg) in peripheral blood during pregnancy, postulating a possible explanation for the effect of progesterone on preterm birth. Cross-sectional study. Tertiary Obstetric Department in a University Hospital. Healthy pregnant women. Treg cells from peripheral blood samples were studied by flow cytometry using multiple monoclonal antibody expression. Evaluate the number and percentage of CD4(+) CD25(high) CD127(low) , the number and percentage of Treg cells among the total CD4(+) T cells, and the percentage and mean fluorescence intensity (MFI) of mPRα in that population, using several gating strategies. 43 peripheral blood samples were collected from healthy women during pregnancy, whose median gestational age was 28.7 ± 7.1 (16-40) weeks. The percentage of CD4(+) in the total lymphocytes was 43% (32-51) and the percentage of CD4(+) CD25(high) CD127(low) was 4.8% (1.6-5.9), with ...
Progesterone: A Unique Hormone with Immunomodulatory Roles in Pregnancy
International Journal of Molecular Sciences, 2022
Progesterone is well known for its numerous endocrinologic roles in pregnancy but is also endowed with fascinating immunomodulatory capabilities. It can downregulate the induction of inflammatory reactions, the activation of immune cells and the production of cytokines, which are critical mediators of immune responses. These features appear to be critical to the success of pregnancy, given the ability of maternal immune reactivity to interfere with pregnancy and to contribute to several pregnancy complications. This review summarizes the contribution of maternal immune effectors in general, and cytokines in particular, to pregnancy complications such as recurrent miscarriage, pre-eclampsia and preterm labor; it describes the promise offered by supplementation with progesterone and the oral progestogen dydrogesterone, as well as the progesterone-induced blocking factor in the prevention and/or treatment of these serious complications.
Progesterone as an immunomodulatory molecule
International Immunopharmacology, 2001
Increased progesterone sensitivity of pregnancy lymphocytes is due to activation-induced appearance of progesterone binding sites in the lymphocytes. Following recognition of fetally derived antigens grd TCR q cells develop progesterone receptors. Progesterone binding results in the synthesis of a mediator protein named the progesterone-induced blocking Ž . factor PIBF . PIBF by acting on the phospholipase A2 enzyme interferes with arachidonic acid metabolism, induces a Th2 biased immune response, and by controlling NK activity exerts an anti-abortive effect. q 2001 Elsevier Science B.V. All rights reserved.