Effects of Progesterone, Dydrogesterone and Estrogen on the Production of Th1/Th2/Th17 Cytokines by Lymphocytes from Women with Recurrent Spontaneous Miscarriage (original) (raw)
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Immunomodulation with progestogens as a therapeutic approach in pregnancy complications
Current Medicine Research and Practice, 2016
Pregnancy is confronted with several challenges such as threatened abortion, spontaneous miscarriage, preeclampsia and preterm delivery. Immunologic effectors have been implicated as contributing to the etiopathogenesis of some of these pregnancy complications. Pro-inflammatory and anti-inflammatory cytokines have been investigated for their effects on the conceptus and pregnancy because of their wide-ranging and potent effects on cells and tissues. This review addresses the nexus between pro-inflammatory cytokines and recurrent miscarriage, which is an important complication of pregnancy. It summarizes the possible mechanisms of action of pro-inflammatory cytokines in pregnancy loss, and then proceeds to discuss immunomodulation of cytokine profiles to a state that is favourable to the success of pregnancy. Fascinating leads for possible redirection of cytokine profiles have come from observations on the immunomodulatory capabilities of progesterone. This review presents studies that show that progesterone and the orally-administered progestogen dydrogesterone inhibit pro-inflammatory cytokines and upregulate anti-inflammatory cytokines; it also summarizes clinical studies on progestogen supplementation. These studies lend credibility to the proposal that progestogens should be explored for the immunotherapeutic management of pregnancy complications.
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.
2003
The purpose of this study was to determine the effects of estradiol and progesterone on interferon-γ (IFN-γ), interleukin (IL)-12, IL-10 and tumor necrosis factor-α (TNF-α) productions in polyclonal activators (phyto hemagglutinin+lipopolysaccharide)-stimulated whole blood cultures. METHODS: Nineteen healthy males and females volunteered in the study. Blood samples were drawn, diluted, and cultured for 24h with different concentrations of estradiol, progesterone or hydrocortisone and then PHA+LPS was added for another 24 h. The supernatant, then, was harvested and assayed for IL-12 p70, IFN-γ, IL-10 and TNF-α. RESULTS: At preovulatory concentrations, estradiol enhanced signifi cantly IFN-γ, IL-12 and IL-10, but not TNF-α, production levels and reversed the suppressive effect of hydrocortisone in PHA+LPS stimulated whole blood. While IL-10 levels kept increasing at pregnancy estradiol concentrations, IFN-γ, IL-12 levels and IFN-γ/IL-10 ratio decreased signifi cantly. No effect of progesterone on IL-12 p70, IFN-γ, IL-10 and TNF production levels was observed. CONCLUSIONS: The present study shows that those pregnancy estradiol concentrations (and higher) enhance the production of IL-10 and reduce IL-12, IFN-γ levels and IFN-γ/IL-10 ratio in stimulated whole blood cells. Because of the known IL-10 inhibitory actions on T helper (Th) 1 cells and monocytes/ macrophages, these high IL-10 levels keep Th2 cytokines favored during pregnancy and may be useful in shifting Th1-mediated autoimmune diseases towards non-pathogenic Th2 pathway.
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 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.
Neuro Endocrinology Letters, 2003
Objectives: The purpose of this study was to determine the effects of estradiol and progesterone on interferon-gamma (IFN-gamma), interleukin (IL)-12, IL-10 and tumor necrosis factor-alpha (TNF-alpha) productions in polyclonal activators (phytohemagglutinin+lipopolysaccharide)-stimulated whole blood cultures. Methods: Nineteen healthy males and females volunteered in the study. Blood samples were drawn, diluted, and cultured for 24h with different concentrations of estradiol, progesterone or hydrocortisone and then PHA+LPS was added for another 24 h. The supernatant, then, was harvested and assayed for IL-12 p70, IFN-gamma, IL-10 and TNF-alpha. Results: At preovulatory concentrations, estradiol enhanced significantly IFN-gamma, IL-12 and IL-10, but not TNF-alpha, production levels and reversed the suppressive effect of hydrocortisone in PHA+LPS stimulated whole blood. While IL-10 levels kept increasing at pregnancy estradiol concentrations, IFN-gamma, IL-12 levels and IFN-gamma/IL-10 ratio decreased significantly. No effect of progesterone on IL-12 p70, IFN-gamma, IL-10 and TNF production levels was observed. Conclusions: The present study shows that those pregnancy estradiol concentrations (and higher) enhance the production of IL-10 and reduce IL-12, IFN-gamma levels and IFN-gamma/IL-10 ratio in stimulated whole blood cells. Because of the known IL-10 inhibitory actions on T helper (Th) 1 cells and monocytes/macrophages, these high IL-10 levels keep Th2 cytokines favored during pregnancy and may be useful in shifting Th1-mediated autoimmune diseases towards non-pathogenic Th2 pathway.
Cytokines, Hormones and Cellular Regulatory Mechanisms Favoring Successful Reproduction
Frontiers in Immunology, 2021
Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune system. Several protective mechanisms operate during gestation to correct the harmful effects of anti-fetal immunity and to support a healthy pregnancy outcome. Pregnancy is characterized by gross alterations in endocrine functions. Progesterone is indispensable for pregnancy and humans, and it affects immune functions both directly and via mediators. The progesterone-induced mediator - PIBF - acts in favor of Th2-type immunity, by increasing Th2 type cytokines production. Except for implantation and parturition, pregnancy is characterized by a Th2-dominant cytokine pattern. Progesterone and the orally-administered progestogen dydrogesterone upregulate the production of Th2-type cytokines and suppress the production of Th1 and Th17 cytokine production in vitro. This is particularly relevant to the fact that the Th1-type cytokines TNF-α and IFN-γ and the Th17 cytokine IL-17 have embryotoxic a...
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...
Neuro endocrinology letters
The purpose of this study was to determine the effects of estradiol and progesterone on interferon-γ (IFN-γ), interleukin (IL)-12, IL-10 and tumor necrosis factor-α (TNF-α) productions in polyclonal activators (phyto hemagglutinin+lipopolysaccharide)-stimulated whole blood cultures. METHODS: Nineteen healthy males and females volunteered in the study. Blood samples were drawn, diluted, and cultured for 24h with different concentrations of estradiol, progesterone or hydrocortisone and then PHA+LPS was added for another 24 h. The supernatant, then, was harvested and assayed for IL-12 p70, IFN-γ, IL-10 and TNF-α. RESULTS: At preovulatory concentrations, estradiol enhanced signifi cantly IFN-γ, IL-12 and IL-10, but not TNF-α, production levels and reversed the suppressive effect of hydrocortisone in PHA+LPS stimulated whole blood. While IL-10 levels kept increasing at pregnancy estradiol concentrations, IFN-γ, IL-12 levels and IFN-γ/IL-10 ratio decreased signifi cantly. No effect of progesterone on IL-12 p70, IFN-γ, IL-10 and TNF production levels was observed. CONCLUSIONS: The present study shows that those pregnancy estradiol concentrations (and higher) enhance the production of IL-10 and reduce IL-12, IFN-γ levels and IFN-γ/IL-10 ratio in stimulated whole blood cells. Because of the known IL-10 inhibitory actions on T helper (Th) 1 cells and monocytes/ macrophages, these high IL-10 levels keep Th2 cytokines favored during pregnancy and may be useful in shifting Th1-mediated autoimmune diseases towards non-pathogenic Th2 pathway.