Targeting FKBP51 prevents stress-induced preterm birth
Ontology highlight
ABSTRACT:
SUBMITTER: Ozlem Guzeloglu Kayisli
PROVIDER: S-SCDT-10_1038-S44321-025-00211-9 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Depression and posttraumatic stress disorder increase the risk of idiopathic preterm birth (iPTB); however, the exact molecular mechanism is unknown. Depression and stress-related disorders are linked to increased FK506-binding protein 51 (FKBP51) expression levels in the brain and/or FKBP5 gene polymorphisms. Fkbp5-deficient (Fkbp5-/-) mice resist stress-induced depressive and anxiety-like behaviors. FKBP51 binding to progesterone (P4) receptors (PRs) inhibits PR function. Moreover, reduced PR activity and/or expression stimulates human labor. We report enhanced in situ FKBP51 expression and increased nuclear FKBP51-PR binding in decidual cells of women with iPTB versus gestational age-matched controls. In Fkbp5+/+ mice, maternal restraint stress did not accelerate systemic P4 withdrawal but increased Fkbp5, decreased PR, and elevated AKR1C18 expression in uteri at E17.25 followed by reduced P4 levels and increased oxytocin receptor (Oxtr) expression at 18.25 in uteri resulting in PTB. These changes correlate with inhibition of uterine PR function by maternal stress-induced FKBP51. In contrast, Fkbp5-/- mice exhibit prolonged gestation and are completely resistant to maternal stress-induced PTB and labor-inducing uterine changes detected in stressed Fkbp5+/+ mice. Collectively, these results uncover a functional P4 withdrawal mechanism mediated by maternal stress-induced enhanced uterine FKBP51 expression and FKPB51-PR binding, resulting in iPTB.
| S-EPMC7980401 | biostudies-literature
Project description:Study questionIs resveratrol able to prevent the lipopolysaccharide (LPS)-induced preterm labor in 15-day pregnant BALB/c mice?Summary answerResveratrol prevented the LPS-induced onset of preterm labor in 64% of the cases and showed anti-inflammatory and tocolytic effects by downregulating COX-2 and iNOS expression and NOS activity, and by changing the uterine prostaglandin and endocannabinoid profiling.What is known alreadyGenital tract infections by Gram-negative bacteria are a common complication in human pregnancy and have been shown to increase risk of preterm delivery. Bacterial LPS elicits a strong maternal inflammatory response that results in preterm delivery and fetal death in a murine model endotoxin-induced preterm labor.Study design, size, durationAn in vivo animal study was conducted. On Day 15 of pregnancy, mice received at 8:00 h a dose of vehicle (40% ethanol in saline solution) or resveratrol (3 mg/kg in vehicle) via oral gavage followed by two doses of LPS or vehicle administered intraperitoneally (i.p.), the first one at 10:00 h (0.17 mg/kg in 0.1 ml of sterile saline solution) and the second at 13:00 h (0.5 mg/kg in 0.1 ml of sterile saline solution). The mice were closely observed for any signs of morbidity (piloerection, decreased movement, and diarrhea), vaginal bleeding or preterm delivery. The beginning of preterm delivery was defined by early delivery of the first pup. Normal term labor occurs on Day 19 of gestation.Participants/materials, setting, methodsTime of labor, pregnancy outcome and morphological features were evaluated after LPS and/or resveratrol administration. Uterine stripes were collected 5 h after the last LPS injection and prostaglandin and endocannabinoid profiling was analyzed by mass spectrometry. Nitric oxide synthase (NOS) activity was measured by radioconversion assay. Cyclooxygenase-2 (Cox-2) and 15-hydroxyprostaglandin dehydrogenase (15-Pgdh) mRNA levels were analyzed by RT-PCR whilst the protein expression of inducible nitric oxide synthase (iNOS), COX-1 and COX-2 were studied by western blot.Main results and the role of chanceIn vivo treatment of 15-day pregnant BALB/c mice with resveratrol prevented the LPS-induced preterm birth in 64% of the cases, whereas only 15% of mice with LPS alone escaped preterm birth. Treatment with resveratrol resulted in a reduced NOS activity (P < 0.05) in the uterus of LPS-treated mice. Similarly, resveratrol reduced the expression of LPS-induced pro-inflammatory agents such as iNOS (P < 0.05), COX-2 (P < 0.05), prostaglandin E2 (PGE2) (P < 0.05) and anandamide (AEA) (P < 0.05). Moreover, resveratrol administration resulted in changes in the uterine endocannabinoid profiling altered by LPS.Large scale dataN/A.Limitations, reasons for cautionSince our experimental design involves the use of mice, the extrapolation of the results presented here to humans is limited.Wider implications of the findingsOur findings provide evidence for the tocolytic effects of resveratrol.Study funding and competing interest(s)Dr Ana María Franchi was funded by Agencia Nacional para la Promoción Científica y Tecnológica (PICT 2013/0097) and by Consejo Nacional de Investigaciones Científicas y Técnicas (PIP 2012/0061). Dr Heather B. Bradshaw was funded by NIH (DA006668). The authors have no competing interests.
| S-EPMC5909859 | biostudies-literature
Project description:FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of the glucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one of the major GR target genes in skin, but its role in clinical effects of glucocorticoids is not known. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in the major adverse effect of topical glucocorticoids, skin atrophy. Unexpectedly, we found that all skin compartments (epidermis, dermis, dermal adipose and CD34+ stem cells) in FKBP51 KO animals were much more resistant to glucocorticoid-induced hypoplasia. Furthermore, despite the absence of inhibitory FKBP51, the basal level of expression and glucocorticoid activation of GR target genes were not increased in FKBP51 KO skin or CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known to negatively regulate Akt and mTOR. We found a significant increase in AktSer473 and mTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usually negative in skin, our results suggest that Akt/mTOR activation could be responsible for the lack of increased GR function and resistance of FKBP51 KO mice to the steroid-induced skin atrophy.
| S-EPMC6205168 | biostudies-literature
Project description:BackgroundOne of every four preterm neonates is born to a woman with sterile intra-amniotic inflammation (inflammatory process induced by alarmins); yet, this clinical condition still lacks treatment. Herein, we utilized an established murine model of sterile intra-amniotic inflammation induced by the alarmin high-mobility group box-1 (HMGB1) to evaluate whether treatment with clarithromycin prevents preterm birth and adverse neonatal outcomes by dampening maternal and fetal inflammatory responses.MethodsPregnant mice were intra-amniotically injected with HMGB1 under ultrasound guidance and treated with clarithromycin or vehicle control, and pregnancy and neonatal outcomes were recorded (n = 15 dams each). Additionally, amniotic fluid, placenta, uterine decidua, cervix, and fetal tissues were collected prior to preterm birth for determination of the inflammatory status (n = 7-8 dams each).ResultsClarithromycin extended the gestational length, reduced the rate of preterm birth, and improved neonatal mortality induced by HMGB1. Clarithromycin prevented preterm birth by interfering with the common cascade of parturition as evidenced by dysregulated expression of contractility-associated proteins and inflammatory mediators in the intra-uterine tissues. Notably, clarithromycin improved neonatal survival by dampening inflammation in the placenta as well as in the fetal lung, intestine, liver, and spleen.ConclusionsClarithromycin prevents preterm birth and improves neonatal survival in an animal model of sterile intra-amniotic inflammation, demonstrating the potential utility of this macrolide for treating women with this clinical condition, which currently lacks a therapeutic intervention.
| S-EPMC9210693 | biostudies-literature
Project description:Acculturation and acculturative stress are potential risk factors for adverse perinatal outcomes. This study investigates whether and how acculturative stress affects preterm birth (PTB) in a sample of migrant women in Berlin. We interviewed 955 women who recently gave birth using standardized questionnaires (Frankfurt Acculturation Scale and Acculturative Stress Index). Multivariable logistic regression analyses assessed the effects of acculturation and acculturative stress on PTB. Women with migrant backgrounds did not have significantly higher PTB rates than German natives. First-generation migrants experienced higher acculturative stress levels than second-generation migrants, 38.8% vs. 13.2%. Acculturative stress could not be identified as a risk factor for PTB in our sample. These results need to be considered in the context of an international city and the wide use of antenatal care services in our population, which could be responsible for similarly good perinatal outcomes and highlights the potential of good access to perinatal care for vulnerable groups.
| S-EPMC10310617 | biostudies-literature
Project description:Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy.
| S-EPMC7279576 | biostudies-literature
Project description:Premature delivery occurs in 12% of all births, and accounts for nearly half of long-term neurological morbidity, and 60% to 80% of perinatal mortality. Despite advances in obstetrics and neonatology, the rate of premature delivery has increased approximately 12% since 1990. The single most common cause of spontaneous preterm birth is infection. Several lines of evidence have demonstrated the role of endothelin-1 as both a constrictor of uterine myometrial smooth muscle and a proinflammatory mediator. Endothelin-1 activates the phospholipase C pathway, leading to activation of protein kinase C and, in turn, sphingosine kinase (SphK). The inhibition of SphK has been recently shown to control the proinflammatory response associated with sepsis. We show herein, for the first time, that SphK inhibition prevents inflammation-associated preterm birth in a murine model. Rescue of pups from premature abortion with an SphK inhibitor occurs by suppression of the proinflammatory cytokines tumor necrosis factor α, Il-1β, and Il-6 and attenuation of polymorphonuclear inflammatory cells into the placental labyrinth. Moreover, we postulate that inhibition of SphK leads to suppression of endothelin-converting enzyme-1 expression, indicating the presence of an endothelin-converting enzyme 1/endothelin 1-SphK positive feedback loop. This work introduces a novel approach for the control of infection-triggered preterm labor, a condition for which there is no effective treatment.
| S-EPMC4348465 | biostudies-literature
Project description:BackgroundPreterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.MethodsProteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping.FindingsIL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis.InterpretationIL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes.FundingNICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.
| S-EPMC10665693 | biostudies-literature
Project description:Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) have anti-inflammatory effects. Preterm birth is an important problem in modern obstetrics and one of the main causes is an inflammation. We here showed that abundance of omega-3 fatty acids reduced the incidence of preterm birth induced by LPS with fat-1 mice, capable of converting omega-6 to omega-3 fatty acids. We also indicated that the gene expression of IL-6 and IL-1β in uteruses and the number of cervical infiltrating macrophages were reduced in fat-1 mice. The analyses of lipid metabolomics showed the high level of 18-hydroxyeicosapentaenoate in fat-1 mice, which was derived from EPA and was metabolized to anti-inflammatory product named resolvin E3 (RvE3). We finally showed that the administration of RvE3 to LPS-exposed pregnant wild type mice lowered the incidence of preterm birth. Our data suggest that RvE3 could be a potential new therapeutic for the prevention of preterm birth.
| S-EPMC3814804 | biostudies-other
Project description:We reviewed the evidence for three theories of how preconceptional psychosocial stress could act as a contributing determinant of excess preterm birth risk among African American women: early life developmental plasticity and epigenetic programming of adult neuroendocrine systems; blunting, weathering, or dysfunction of neuroendocrine and immune function in response to chronic stress activation through the life course; individuals' adoption of risky behaviors such as smoking as a response to stressful stimuli.Basic science, clinical, and epidemiologic studies indexed in MEDLINE and Web of Science databases on preconceptional psychosocial stress, preterm birth and race were reviewed.Mixed evidence leans towards modest associations between preconceptional chronic stress and preterm birth (for example common odds ratios of 1.2-1.4), particularly in African American women, but it is unclear whether this association is causal or explains a substantial portion of the Black-White racial disparity in preterm birth. The stress-preterm birth association may be mediated by hypothalamic-pituitary-adrenal axis dysfunction and susceptibility to bacterial vaginosis, although these mechanisms are incompletely understood. Evidence for the role of epigenetic or early life programming as a determinant of racial disparities in preterm birth risk is more circumstantial.Preconceptional stress, directly or in interaction with host genetic susceptibility or infection, remains an important hypothesized risk factor for understanding and reducing racial disparities in preterm birth. Future studies that integrate adequately sized epidemiologic samples with measures of stress, infection, and gene expression, will advance our knowledge and allow development of targeted interventions.
| S-EPMC5573146 | biostudies-other