RESUMEN
Growth differentiation factor-15 (GDF15) is a stress-responsive cytokine that plays important roles in regulation of inflammatory responses, cell growth, and cell differentiation. However, the nature of these roles remains unclear. Here, we aimed to examine the regulatory effects of dexamethasone on Gdf15 expression in murine AtT-20 corticotroph cells. Human Gdf15 promoter-driven luciferase reporter constructs were transfected into corticotroph cells to analyze their promoter activity. The effects of time and concentration of dexamethasone on Gdf15 and proopiomelanocortin (Pomc) mRNA levels were assessed using quantitative real-time polymerase chain reaction. Dexamethasone induced Gdf15 transcription and mRNA levels as well as GDF15 production in transfected cells, whereas reduced the Pomc mRNA levels. GDF15 modulated adrenocorticotropic hormone (ACTH) synthesis, and the dexamethasone-mediated reduction in Pomc mRNA levels were partially relieved upon Gdf15 knockdown. We concluded that GDF15 modulated ACTH production in pituitary corticotrophs in an autocrine manner by suppressing Pomc expression and subsequently mediating the negative feedback effect of glucocorticoids, thereby contributing to pituitary stress response and homeostasis.
Asunto(s)
Hormona Adrenocorticotrópica , Corticotrofos , Factor 15 de Diferenciación de Crecimiento , Hormona Adrenocorticotrópica/metabolismo , Animales , Corticotrofos/química , Corticotrofos/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Dexametasona/farmacología , Expresión Génica , Factor 15 de Diferenciación de Crecimiento/metabolismo , Humanos , Ratones , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The purpose of this study was to investigate the expression of bone morphogenetic protein 4 (BMP4) and its receptors, bone morphogenetic protein receptor I (BMPRI) and BMPRII, in the pituitary gland of healthy adult dogs and in those with ACTH-secreting pituitary adenoma. Quantitative polymerase chain reaction analysis showed that the BMP4 messenger RNA expression level in the ACTH-secreting pituitary adenoma samples was significantly lower than that in the normal pituitary gland samples (P = 0.03). However, there were no statistically significant differences between samples with respect to the messenger RNA expression levels of the receptors BMPRIA, BMPRIB, and BMPRII. Double-immunofluorescence analysis of the normal canine pituitary showed that BMP4 was localized in the thyrotroph (51.3 ± 7.3%) and not the corticotroph cells. By contrast, BMPRII was widely expressed in the thyrotroph (19.9 ± 5.2%) and somatotroph cells (94.7 ± 3.6%) but not in the corticotroph cells (P < 0.001, thyrotroph cells vs somatotroph cells). Similarly, in ACTH-secreting pituitary adenoma, BMP4 and BMPRII were not expressed in the corticotroph cells. Moreover, the percentage of BMP4-positive cells was also significantly reduced in the thyrotroph cells of the surrounding normal pituitary tissue obtained from the resected ACTH-secreting pituitary adenoma (8.3 ± 7.9%) compared with that in normal canine pituitary (P < 0.001). BMP4 has been reported to be expressed in corticotroph cells in the human pituitary gland. Therefore, the results of this study reveal a difference in the cellular pattern of BMP4-positive staining in the pituitary gland between humans and dogs and further revealed the pattern of BMPRII-positive staining in the dog pituitary gland. These species-specific differences regarding BMP4 should be considered when using dogs as an animal model for Cushing's disease.
Asunto(s)
Adenoma Hipofisario Secretor de ACTH/veterinaria , Proteína Morfogenética Ósea 4/genética , Enfermedades de los Perros/metabolismo , Expresión Génica , Hipófisis/metabolismo , Adenoma Hipofisario Secretor de ACTH/química , Adenoma Hipofisario Secretor de ACTH/metabolismo , Animales , Proteína Morfogenética Ósea 4/análisis , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/análisis , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/análisis , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Corticotrofos/química , Modelos Animales de Enfermedad , Perros , Femenino , Técnica del Anticuerpo Fluorescente/veterinaria , Humanos , Masculino , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Hipófisis/química , ARN Mensajero/análisis , Tirotrofos/químicaRESUMEN
Hypoplasia adrenal congenita is an extremely uncommon disease of early onset. This condition can be lethal in the absence of treatment. Some forms are due to the congenital adrenal hypoplasia of anencephalic type whose origin is even unknown. Here, we present two cases of congenital adrenal hypoplasia of anencephalic type with pituitary abnormalities. The two male newborns died because adrenal insufficiency in the neonatal period. The adrenal glands were hypoplastic with a histological structure of anencephalic type Immunocytochemical study of the pituitary revealed an absence of the gonadotrophs. No mutation of DAX 1 and SF-1 was found.
Asunto(s)
Anomalías Múltiples/patología , Anencefalia/patología , Hipófisis/anomalías , Glándulas Suprarrenales/ultraestructura , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/patología , Insuficiencia Suprarrenal , Corteza Cerebral/patología , Corticotrofos/química , Corticotrofos/ultraestructura , Receptor Nuclear Huérfano DAX-1/genética , Proteínas de Unión al ADN/genética , Resultado Fatal , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Genitales Femeninos/patología , Genitales Masculinos/patología , Gonadotrofos/patología , Humanos , Insuficiencia Corticosuprarrenal Familiar , Recién Nacido , Cariotipificación , Masculino , Adenohipófisis/química , Adenohipófisis/ultraestructura , Neurohipófisis/anomalías , Factores de Empalme de ARN , Técnicas Reproductivas Asistidas , Factores de Transcripción/genética , Vacuolas/ultraestructuraRESUMEN
We have studied here the cellular distribution of several regulatory peptides in hormone-producing cells of the human pituitary during the fetal period. Immunohistochemistry was used to show the expression of several regulatory peptides, namely Angiotensin-II, Neurotensin and Galanin, at successive gestational stages and their co-localization with hormones in the human fetal adenohypophysis. Somatotrophs, gonadotrophs and thyrotrophs were differentiated earliest. At gestational week 9, Angiotensin-II immunoreactivity was co-localized only with growth hormone immunoreactivity in somatotrophs, one of the first hormone-producing cells to differentiate. This co-localization remained until week 37. Neurotensin immunoreactivity was present in gonadotrophs and thyrotrophs in week 23, after FSH and TSH hormone differentiation. Galanin immunoreactivity was present in all hormone-producing cell types except corticotrophs. The different pro-opiomelanocortin-derived peptides were detected at different stages of gestation and adrenocorticotrophic hormone immunoreaction was the last to be detected. Our results show an interesting relationship between regulatory peptides and hormones during human fetal development, which could imply that these peptides play a regulatory role in the development of pituitary function.
Asunto(s)
Angiotensina II/análisis , Galanina/análisis , Neurotensina/análisis , Adenohipófisis/embriología , Hormona Adrenocorticotrópica/análisis , Diferenciación Celular , Corticotrofos/química , Edad Gestacional , Gonadotrofos/química , Humanos , Inmunohistoquímica , Adenohipófisis/química , Somatotrofos/química , Tirotrofos/químicaRESUMEN
This study assesses the action of hypercortisolism on the hormone and peptide periadenoma region of removed ACTH-producing microadenoma. Our findings show that cortisol excess affects both ACTH and GH production, with no immunoreaction for these hormones. The remaining pituitary hormones (TSH, FSH and PRL) and POMC-derived peptides (betaEnd, alphaMSH and betaMSH) were not modified. Likewise, we observed pituitary immunoreactive cells for Neurotensin (NT), Intestinal vasoactive peptide (VIP), Substance P (SP) and Angiotensin-II (Ang-II). The colocalization demonstrated that NT was expressed in thyrotrope and gonadotrope cells, VIP in gonadotrope cells and SP in corticotrope cells. The results about Ang-II were inconclusive. On the other hand, immunoreaction for the NPY and Gal peptides were not present. In the adenomatous cells, the peptide NT is present in ACTH cells as well as SP. These results suggest a peptide regulation of pituitary cells in the pathological state that can differ between normal and tumoural cells of the same pituitary.