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Steroidrezeptoren und microRNAWe hypothesize that non steroid hormone receptor schwannomas VS exhibit up-regulation of estrogen receptor ER at the protein level compared to control Great auricular nerve GAN. It has been reported in the literature that VS occur more commonly in women, tend steroids test be larger and more vascular in women, and growth rate best testosterone booster estrogen blocker accelerate during pregnancy. The rdceptor contains widely divergent results on ER expression in VS, however, varying from no detectable levels to detection of ER in all samples. VS specimens exhibited more pronounced up-regulation of non steroid hormone receptor ie. Further investigation into antiestrogen therapy for VS is warranted. VS are typically encapsulated and histologically benign, but can cause pressure damage to nearby cranial nerves, resulting in cranial neuropathies. Hearing loss is the most common presenting symptom, due to compression of the adjacent cochlear nerve.
Estrogen Receptor Expression in Sporadic Vestibular Schwannomas
As a bystander effect, pregnancy also potently suppresses the activity of the autoimmune disease multiple sclerosis MS. Here, we report that T cells are able to directly sense progesterone via their glucocorticoid receptor GR , resulting in an enrichment of regulatory T cells Tregs. By using an MS animal model, we found that the presence of the GR in T cells is essential to increase Tregs and confer the protective effect of pregnancy, but not for maintaining the pregnancy itself.
Better understanding of this tolerogenic pathway might yield more specific therapeutic means to steer the immunological balance in transplantation, cancer, and autoimmunity. Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis MS is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms.
Here, we investigated the endocrine regulation of conventional and regulatory T cells Tregs during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor GR in T cells.
In vivo, T-cell—specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis EAE , the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.
Reproduction is fundamental to the maintenance and evolution of species. To ensure successful pregnancy, mothers have to establish robust immunological tolerance toward the semiallogeneic conceptus providing a secure niche for fetal development.
Multiple mechanisms have evolved to prevent fetus-directed immune responses and alloreactive infiltration of the fetomaternal interface 1. Intriguingly, pregnancy is also well known to suppress the inflammatory activity of a number of cell-mediated autoimmune diseases, including rheumatoid arthritis 6 , 7 , autoimmune hepatitis 8 , and multiple sclerosis MS 9 , However, this beneficial effect is limited to the period of gestation and usually followed by a rebound of disease activity postpartum.
In the case of MS, third trimester pregnancy leads to a remarkable reduction of the MS relapse rate 11 , which exceeds the effects of most currently available disease-modifying drugs.
Tregs are characterized by the transcription factor forkhead box P3 Foxp3 and effectively control effector responses mounted by Tcons in response to antigen-specific activation. In the context of pregnancy, Tregs were shown to expand to safeguard against fetal rejection by establishing antigen-directed immunological tolerance 18 , Depletion of Tregs results in fetal loss Pregnancy-related hormonal signals, including estrogens and progesterone 1 , 24 , 25 , appear to support Treg proportion and function, although their exact mode of action remains incompletely understood.
In the context of autoimmunity, Tregs are essential in suppressing autoreactive responses. Beyond that, quantitative or functional Treg impairment has been described in a number of autoimmune diseases, including systemic lupus erythematosus 6 , 7 , 28 , 29 , rheumatoid arthritis 8 , 30 , 31 , and type I diabetes 9 , 10 , However, it is still unknown which pregnancy-related changes account for the enhanced control of autoreactive responses.
Here, we sought to unravel the molecular mechanisms that confer the beneficial effect of pregnancy on autoimmunity. By studying the impact of pregnancy and pregnancy hormones on T-cell subsets including Tregs, we provide evidence that differential sensitivity to glucocorticoid receptor GR activity is a hitherto unrecognized mechanism shaping the T-cell compartment.
By targeted GR deletion in T cells, we show a selective disruption of pregnancy-induced protection from autoimmunity. We first characterized the relative abundance and phenotype of Tcons and Tregs throughout pregnancy and postpartum time points Fig.
We analyzed cells from paraaortic lymph nodes LNs , inguinal lymph nodes, and spleen to get insight into local, regional, and systemic changes, respectively Fig. The acquired data indicated that Treg expansion was most pronounced in the paraaortic lymph nodes that drain the fetomaternal interface.
We observed two proliferative bursts of Tregs in early E2. In line with this observation, the first expansion was limited to the local paraaortic lymph nodes, whereas the second was also detectable in regional inguinal lymph nodes and systemically in the spleen Fig. Additionally, late pregnancy Tregs consistently showed increased expression of the immunosuppressive molecule CTLA-4 in all assessed organs, rendering them potentially more effective in controlling effector responses Fig.
Treg dynamics during pregnancy. Gray shaded areas represent pregnancy. A Time course of allogeneic mating, sample collection, and progesterone serum levels.
B Overview of harvested lymphoid tissue in relation to pregnant uterus. C Representative dot plots of Treg frequency in paraaortic LNs. D Quantification of Treg frequency in indicated tissues. E Phenotypic characterization of Tregs. Data are pooled from multiple experimental days.
Tcon phenotype throughout pregnancy. Together, the Treg response commenced in early gestation with a local proliferative burst and generalized toward systemic compartments in late gestation. Late gestational Tregs showed increased expression of CTLA-4, potentially supporting their suppressive function.
Additionally, progesterone has been shown to have beneficial effects in EAE 18 , 22 , 40 and to expand Treg frequencies upon in vivo treatment Therefore, we tested the ability of progesterone to influence the ratio of Tregs and Tcons in splenocyte cultures.
We could inhibit this effect by the steroid hormone receptor antagonist mifepristone RU , suggesting a defined receptor-mediated rather than a pleiotropic effect. Importantly, RU alone as well as the pregnancy hormone estradiol had no effect on Treg frequencies Fig. At the same time, we observed increased cell death in progesterone-treated cultures paralleling the enrichment of Tregs in a dose-dependent manner Fig.
Prolonged cultivation amplified the effect Fig. Because splenocyte cultures contain different immune cell types that could in principle be involved in sensing progesterone and mediating this finding, we sought to define the target cells of progesterone. T-cell—intrinsic sensing of progesterone mediates Treg enrichment in vitro. Cultures were analyzed for Treg frequency and cell death by flow cytometry. B Dose titration of splenocytes cultured and analyzed as described in A. D Time course of splenocytes cultured and analyzed as described in A.
F Splenocytes were cultured as in A but analyzed after 6 h for apoptosis markers Annexin V and aCasp3. Dot plots in A are representative of at least three independently analyzed animals. Data in C show one representative animal out of five all animals are shown Fig. Estradiol and mifepristone fail to enrich Tregs in vitro.
Progesterone serves as a positive control. Five individual mice are shown. Indeed, both markers showed an increase in apoptosis after progesterone treatment, which was abolished in the presence of RU Fig.
Thus, T-cell—intrinsic sensing of progesterone via a RUblockable receptor resulted in a shift of the immunological balance in favor of Tregs. Our data suggested the existence of a RUblockable receptor in T cells that is engaged by progesterone and induces an enrichment of Tregs in vitro. Because steroid hormones are known to possess promiscuous binding activity to other steroid receptors 41 , we reasoned that progesterone might signal via the GR as an alternative receptor.
Progesterone acts via promiscuous binding to the glucocorticoid receptor. Cultures were analyzed for Treg frequency by flow cytometry. Cultures were analyzed for Treg frequency D and cell death E.
Data in A are pooled from multiple experimental days. To definitely pinpoint a contribution of GR engagement to the observed Treg enrichment, we made use of a T-cell—specific GR knockout mouse.
After ruling out a priori differences in their immune cell composition Fig. This complete rescue in the GR knockout cultures also applied to the induction of apoptosis Fig. S3 A and B , whereas Treg enrichment by both progesterone and DEX was still readily observed in progesterone receptor knockout cultures Fig. In line with our previous experiments, these data support a direct action of progesterone on the GR in T cells to mediate Treg enrichment in vitro.
To test the effect of GR engagement on T cells in vivo, we treated wild-type animals with a single i. Targeted GR deficiency in T cells rescues steroid-driven apoptosis, whereas progesterone receptor is not required for Treg enrichment in vitro. Data in A — C are pooled from two independent experiments each. Dexamethasone increases Treg frequencies via GR in T cells in vivo. A Wild-type mice were treated with one i. Paraaortic LNs, inguinal LNs, and spleen were harvested and Treg frequencies were analyzed by flow cytometry.
We conclude that Treg enrichment upon steroid challenge was mediated via the GR in T cells, whereas we found no indication for an involvement of the PR. For example, it is conceivable that Tcons are more sensitive to glucocorticoid-induced cell death, whereas Tregs are in comparison steroid resistant and hence accumulate. This notion was supported by our observation that cell death dye-positive cells were exclusively present in the Tcon but not in the Treg compartment Fig.
To further substantiate this hypothesis, we isolated Tregs and Tcons and cultured them separately in the presence of increasing doses of DEX as a potent GR stimulus. Tregs are more resistant to GR challenge than Tcons. Cultures were analyzed for cell death dye positivity inside Tcon and Treg populations. B Proliferation response curves of Tregs and Tcons. Proliferation was assessed by [ 3 H]-thymidine incorporation and normalized to vehicle control EtOH.
Curve fit, curve top, and curve bottom values were computed. Dead cells were identified by propidium iodide positivity and cell death was calculated as fold change relative to vehicle control EtOH. Data in A are reanalyzed from Fig. We selected Gilz because its transcription is directly induced by binding of the GR to the Gilz promoter 45 , 46 , it mediates the antiproliferative activity of glucocorticoids 47 , and can be used as a surrogate marker for GR activity.
Additionally, GR signaling was more active in Tcons irrespective of pregnancy, further supporting the notion that those cells might be a priori more susceptible to steroid challenge. Taken together, Tregs showed a higher resistance to glucocorticoid challenges under both proliferative and nonproliferative conditions. This finding is consistent with a positive selection of Tregs as the underlying mechanism for increased Treg frequencies after GR stimulation.
Next, we aimed to unravel whether GR activity in T cells is responsible for the beneficial effect of pregnancy on CNS autoimmunity. We expected the delivery of the pups around day 12 after immunization and included nonpregnant females as controls Fig.
Immediately after birth of the pups, the dams succumbed to an exaggerated disease course associated with increased motor disability and higher mortality, reminiscent of the overshooting disease activity observed in MS patients postpartum Fig. Late pregnancy temporarily protects from CNS autoimmunity.
Universitätsklinikum Halle(Saale): Steroidrezeptoren und microRNA
Übersetzung im Kontext von „ein Steroid, ein Hormon“ in Deutsch-Englisch von is a steroid hormone, a local anaesthetic, an antipyretic analgesic, a non-steroid porphyrins, receptor ligands, steroids, lipids, hormones, peptides, proteins. Übersetzung im Kontext von „sex steroid“ in Englisch-Deutsch von Reverso WITH A SELECTIVE ESTROGEN RECEPTOR MODULATOR AND/OR WITH compound and a non-adrenal inhibitor of sex steroid formation are included. Greene GL () Immunochemical studies of estrogen receptor. In: Roy AK In: Sutherland RL, Jordan VC (eds) Non-steroidal antioestrogens. Academic.