RESUMEN
Galectin-1 (gal-1) is expressed at the feto-maternal interface and plays a role in regulating the maternal immune response against placental alloantigens, contributing to pregnancy maintenance. Both decidua and placenta contribute to gal-1 expression and may be important for the maternal immune regulation. The expression of gal-1 within the placenta is considered relevant to cell-adhesion and invasion of trophoblasts, but the role of gal-1 in the immune evasion machinery exhibited by trophoblast cells remains to be elucidated. In this study, we analyzed gal-1 expression in preimplantation human embryos and first-trimester decidua-placenta specimens and serum gal-1 levels to investigate the physiological role played by this lectin during pregnancy. The effect on human leukocyte antigen G (HLA-G) expression in response to stimulation or silencing of gal-1 was also determined in the human invasive, proliferative extravillous cytotrophoblast 65 (HIPEC65) cell line. Compared with normal pregnant women, circulating gal-1 levels were significantly decreased in patients who subsequently suffered a miscarriage. Human embryos undergoing preimplantation development expressed gal-1 on the trophectoderm and inner cell mass. Furthermore, our in vitro experiments showed that exogenous gal-1 positively regulated the membrane-bound HLA-G isoforms (HLA-G1 and G2) in HIPEC65 cells, whereas endogenous gal-1 also induced expression of the soluble isoforms (HLA-G5 and -G6). Our results suggest that gal-1 plays a key role in pregnancy maternal immune regulation by modulating HLA-G expression on trophoblast cells. Circulating gal-1 levels could serve as a predictive factor for pregnancy success in early human gestation.
Asunto(s)
Aborto Espontáneo/inmunología , Decidua/inmunología , Galectina 1/inmunología , Antígenos HLA-G/inmunología , Placenta/inmunología , Trofoblastos/inmunología , Aborto Espontáneo/sangre , Aborto Espontáneo/diagnóstico , Aborto Espontáneo/genética , Adulto , Biomarcadores/sangre , Blastocisto/inmunología , Adhesión Celular/inmunología , Línea Celular , Decidua/metabolismo , Implantación del Embrión/inmunología , Femenino , Galectina 1/sangre , Galectina 1/genética , Expresión Génica/inmunología , Antígenos HLA-G/sangre , Antígenos HLA-G/genética , Humanos , Evasión Inmune , Tolerancia Inmunológica , Isoantígenos/inmunología , Placenta/metabolismo , Embarazo , Primer Trimestre del Embarazo , Pronóstico , Isoformas de Proteínas/sangre , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Trofoblastos/metabolismoRESUMEN
Cognitive impairments, including spatial memory and learning deficiencies, are common after ischemic stroke. Estrogen substitution improves cognitive functions in post-menopausal women and ovariectomized rodents, partially through induction of neuroplasticity in the hippocampal formation. Post-ischemic housing of male rats in an enriched environment (EE) improves functional outcome, without changing infarct volume. We hypothesized that 17beta-estradiol combined with an EE would accelerate cognitive recovery after focal brain ischemia in ovariectomized rats and that recovery would be related to altered expression of nerve growth factor-induced gene (NGFI)-A in the hippocampus. 17beta-estradiol or placebo pellets were implanted 6 h after transient middle cerebral artery occlusion. Two days later, rats were placed in an EE or a deprived environment (DE) for 6 weeks. At 5 weeks after middle cerebral artery occlusion, 17beta-estradiol-treated rats housed in an EE showed improvements in cognitive function (i.e. shorter latency and path in the Morris water maze task) compared with placebo-treated animals housed in an EE. Furthermore, beneficial effects on latency and path were observed when comparing EE-housed vs. DE-housed 17beta-estradiol-treated rats. When comparing 17beta-estradiol-treated EE-housed rats vs. placebo-treated DE-housed rats, pronounced effects on latency and path were observed. Infarct volumes did not differ between groups. 17beta-estradiol-treated EE-housed rats had significantly higher NGFI-A mRNA expression bilaterally in the cornu ammonis 1 region and in the ipsilateral dentate gyrus of the hippocampus, compared with placebo-treated EE-housed rats. In conclusion, 17beta-estradiol treatment combined with an EE improved recovery of cognitive function after experimental brain ischemia, putatively through the upregulation of NGFI-A in hippocampal subregions.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/enfermería , Ambiente , Estradiol/uso terapéutico , Estrógenos/uso terapéutico , Recuperación de la Función/efectos de los fármacos , Análisis de Varianza , Animales , Infarto Encefálico/tratamiento farmacológico , Infarto Encefálico/etiología , Isquemia Encefálica/complicaciones , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Estradiol/sangre , Estrógenos/sangre , Femenino , Lateralidad Funcional/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Pruebas Neuropsicológicas , Ovariectomía/métodos , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Recuperación de la Función/fisiología , Sensación/efectos de los fármacos , Factores de Tiempo , Vibrisas/efectos de los fármacos , Vibrisas/inervaciónRESUMEN
BACKGROUND: Signaling through estrogen receptor alpha (ER alpha) regulates vasodilatation and atherogenesis. Since hypertension and atherosclerosis are major mechanisms in stroke development, we hypothesized that genetic variants of the ER alpha gene (ESR1) are determinants of future ischemic stroke or intracerebral hemorrhage (ICH). METHODS: In a population-based prospective nested case-control study, the relationships between ESR1 polymorphisms (c.454-397T>C and c.454-351A>G) and ischemic stroke and ICH were examined in univariate and multivariate models using conditional logistic regression, which included established risk factors.Definitive first-ever stroke events (n = 388), including ischemic stroke (n = 320), ICH (n = 61), and unspecified stroke (n = 7) cases, and controls without cardiovascular disease (n = 773), matched for age, sex, and geographical region were included. RESULTS: Carriers of the c.454-397T/T genotype had a significantly (p = 0.017) increased risk of ICH (OR 2.31, 95% CI 1.16-4.60) in a univariate analysis. This association persisted (OR 3.94, 95% CI 1.54-10.03), after adjustment for stroke risk determinants. Carriers of c.454-397T/T or c.454-397T/C genotypes had significantly (p = 0.002 and p = 0.004, respectively) higher mean systolic blood pressure (SBP), than carriers of c.454-397C/C, and a similar relationship was observed for diastolic blood pressure (DBP). The combinations of c.454-397T/T genotype and hypertension (OR 21.46, 95% CI 5.20-88.51), or high SBP (OR 18.17, 95% CI 4.91-67.31) or DBP (OR 11.94, 95% CI 3.75-38.03), were strongly associated with increased risk of ICH. CONCLUSIONS: In this population,the c.454-397T/T genotype associates with first-ever ICH, particularly in combination with hypertension. This implies that alterations in ER alpha-mediated signaling may be involved in the pathophysiology of this disease, with a putative impact on primary prevention.
Asunto(s)
Isquemia Encefálica/complicaciones , Hemorragia Cerebral/genética , Receptor alfa de Estrógeno/genética , Polimorfismo Genético , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/genética , Anciano , Secuencia de Bases , Presión Sanguínea/genética , Estudios de Casos y Controles , Hemorragia Cerebral/etiología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Estudios ProspectivosRESUMEN
PROBLEM: Regulatory T cells (Treg cells), a small subset of CD4(+) T cells maintaining tolerance by immunosuppression, are proposed contributors to the survival of the fetal semiallograft. We investigated Treg cells in paired decidual and peripheral blood (PB) samples from healthy women in early pregnancy and PB samples from non-pregnant women. METHOD OF STUDY: Distribution, location, cytokine mRNA, and phenotype were assessed in CD4(+) CD25(+) Treg cells from paired samples using immunohistochemistry, immunofluorescence, flow cytometry, and real-time quantitative RT-PCR. RESULTS: The presence and in situ distribution of CD4(+) Foxp3(+) Treg cells in decidua are hereby demonstrated for the first time. Three Foxp3(+) cell populations, CD4(+) CD25(++) Foxp3(+), CD4(+) CD25(+) Foxp3(+), and CD4(+) CD25(-) Foxp3(+), were enriched locally in decidua. In contrast, no statistically significant difference in numbers of circulating Treg cells between pregnant and non-pregnant women was found. The Foxp3(+) cells expressed the surface molecules CD45RO, CTLA-4, CD103, Neuropilin-1, LAG-3, CD62L, and TGFß1 mRNA consistent with Treg phenotype. The population of CD4(+) CD25(-) Foxp3(+) cells, not described in human decidua before, was enriched 10-fold compared with PB in paired samples. Their cytokine expression was often similar to Th3 profile, and the Foxp3 mRNA expression level in CD4(+) CD25(-) cells was stable and comparable to that of CD4(+) CD25(+) Treg cells implying that the majority of CD4(+) CD25(-) Foxp3(+) cells might be naïve Treg cells. CONCLUSION: (i) There is a local enrichment of Treg cells in decidua (ii) The exclusive accumulation of decidual CD4(+) CD25(-) Foxp3(+) cells suggests an additional reservoir of Foxp3(+) naïve Treg cells that can be converted to 'classical' Treg cells in uterus.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Decidua/inmunología , Factores de Transcripción Forkhead/biosíntesis , Ligando OX40/inmunología , Embarazo/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos CD/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Citocinas/genética , Citocinas/metabolismo , Decidua/metabolismo , Femenino , Factores de Transcripción Forkhead/genética , Humanos , Neuropilina-1/genética , Neuropilina-1/metabolismo , Ligando OX40/biosíntesis , Fenotipo , Embarazo/sangre , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11betaHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11betaHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11betaHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5alpha-tetrahydrocortisol+5beta-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11betaHSD1 activity. Postmenopausal women had higher 11betaHSD1 gene expression in subcutaneous fat (P<0.05). Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion), suggesting higher hepatic 11betaHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11betaHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Peso Corporal/fisiología , Especificidad de Órganos/fisiología , Posmenopausia/fisiología , Tejido Adiposo/enzimología , Corticoesteroides/sangre , Corticoesteroides/orina , Adulto , Aromatasa/genética , Aromatasa/metabolismo , Femenino , Regulación Enzimológica de la Expresión Génica , Humanos , Lípidos/sangre , Hígado/enzimología , Persona de Mediana Edad , Posmenopausia/sangre , Posmenopausia/orina , ARN Mensajero/genética , ARN Mensajero/metabolismo , Tejido Subcutáneo/enzimologíaRESUMEN
BACKGROUND: Arterial calcification and osteoporosis often coexist, especially in postmenopausal women. Osteoporosis associates with a substantially increased risk of stroke in elderly women, suggesting that impaired estrogen signaling may link stroke and osteoporosis. Osteoprotegerin (OPG, TNFRSF11B) and interleukin-6 (IL-6, IL6) are putative target genes for estrogen signaling and have been implicated in both cardiovascular diseases and osteoporosis. We hypothesized that specific polymorphisms in these genes may be associated with increased risk of ischemic stroke or intracerebral hemorrhage (ICH). METHODS: We performed a population-based prospective nested case-control study, in which the relationships between polymorphisms (OPG-1181G/C, OPG-950T/C and IL6-174G/C) and ischemic stroke and ICH were examined. Definitive first-ever stroke events (n = 388), i.e. ischemic stroke (n = 320), ICH (n = 61) and unspecified stroke (n = 7) cases, and controls without cardiovascular disease (n = 773), matched for age, sex and geographical region were studied. Univariate and multivariate models using conditional logistic regression, which included traditional risk factors, were used to test for association. RESULTS: Carriers of the OPG-1181C/C genotype had a significantly (p = 0.018) increased risk of ICH (OR, 2.69; 95% CI, 1.19-6.12) in the univariate analysis. After adjustments (hypertension, diabetes, BMI and triglycerides), this genotype remained significantly (p = 0.005) associated with ICH (OR, 6.04; 95% CI, 1.71-21.29). By contrast, no correlations were found between this genotype and ischemic stroke, nor between the OPG-950T/C or IL6-174G/C polymorphisms and stroke subtypes. CONCLUSIONS: In this population, the OPG-1181C/C genotype associates with first-ever ICH, implying that alterations in OPG-mediated signaling in the vasculature may be involved in the pathophysiology of this disease.
Asunto(s)
Isquemia Encefálica/complicaciones , Hemorragia Cerebral/genética , Interleucina-6/genética , Osteoprotegerina/genética , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/genética , Adulto , Anciano , Isquemia Encefálica/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Encuestas Epidemiológicas , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , SueciaRESUMEN
OBJECTIVE: Causes of visceral fat accumulation include glucocorticoid excess or decreased oestrogen/androgen ratio either in plasma or within adipose tissue. In obese subjects, the intra-adipose cortisol-generating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is increased, but information on sex steroid signalling is sparse. We aimed to test associations between body fat or fat distribution and mRNA transcript levels for androgen and oestrogen receptors and for enzymes metabolizing sex steroids in adipose tissue. DESIGN: A cross-sectional study. PATIENTS: Forty-five healthy men and women with body mass index (BMI) 21-36 kg/m(2). MEASUREMENTS: In subcutaneous adipose biopsies we measured mRNAs for enzymes metabolizing local oestrogens (aromatase) and androgens [5alpha-reductase type 1; AKR1C2 (3alpha-HSD3); AKR1C3 (17beta-HSD5, 3alpha-HSD2)] and for sex steroid receptors [oestrogen receptor (ER)-alpha and androgen receptor (AR)]. We related these to body fat mass and distribution. RESULTS: Generalized obesity (BMI) was associated with increased aromatase mRNA (r = 0.35, P < 0.05). Central obesity (waist : hip ratio) was associated with mRNA for AKR1C2 (r = 0.28, P < 0.05) and AKR1C3 (r = 0.38, P < 0.01) but not aromatase (r = 0.06). 5alpha-Reductase type 1, ER and AR mRNA levels did not predict fat amount or its distribution. CONCLUSION: These data on transcript levels suggest that, in idiopathic obesity, increased intra-adipose oestrogen generation by aromatase predicts peripheral fat distribution, while androgen metabolism by AKR1C isoforms predicts central fat distribution, supporting the hypothesis that intra-adipose sex steroid metabolism is a determinant of gynoid vs. android patterns of body fat.