RESUMO
The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.
Assuntos
Comunicação Celular/fisiologia , Hipófise/citologia , Hipófise/fisiologia , Transdução de Sinais/fisiologia , Animais , Sistema Endócrino/fisiologia , Homeostase/fisiologia , Hormônios/metabolismo , Humanos , Sistemas Neurossecretores/fisiologiaRESUMO
Research performed on the pituitary has proven that cytokines play an important role in maintaining pituitary physiology, affecting not only cell proliferation but also hormone secretion. The effects of cytokines can be autocrine or paracrine. This review gives an overview on the effects of the most studied cytokines in the pituitary. Special interest is focused on interleukin-6 (IL-6) because it has the distinctive characteristic of stimulating pituitary tumor cell growth, but has the opposite effect on normal pituitary cells. On the other hand, IL-6 is a cytokine of interest in the pituitary because recent work has shown that it promotes and maintains senescence in certain types of tumors. Given that the majority of pituitary adenomas are microadenomas and the fact that clinically inapparent pituitary tumors are quite common, senescence, perhaps mediated by IL-6, is an attractive mechanism for explaining the benign nature of pituitary tumors.
Assuntos
Citocinas/fisiologia , Hipófise/fisiologia , Adenoma/etiologia , Animais , Senescência Celular/fisiologia , Citocinas/metabolismo , Humanos , Interleucina-6/fisiologia , Modelos Biológicos , Hipófise/crescimento & desenvolvimento , Hipófise/metabolismo , Hipófise/patologia , Neoplasias Hipofisárias/etiologiaRESUMO
OBJECTIVE: In a previous study, we reported an imbalance in the hypothalamus-pituitary-adrenal axis of mice acutely infected with the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. METHODS: Possible effects of this parasitic infection on the endocrine function of other pituitary cell types were studied, in particular regarding the production of prolactin (PRL) and growth hormone (GH). RESULTS: In the mammosomatotrophic cell line GH3, both GH and PRL secretion were decreased, reflecting the diminished PRL concentrations in the pituitary glands of infected mice. Additionally, expression of extracellular matrix proteins, e.g. laminin, was increased in T. cruzi-infected GH3 cells, which may be related to the diminished secretory function of these cells. Lastly, the expression of Pit-1, a major transcription factor for the PRL and GH genes, is also decreased in T. cruzi-infected cultures. CONCLUSION: T. cruzi infection downregulates PRL and GH production. Combined with our previous data showing increased glucocorticoid levels following T. cruzi infection, the immunosuppression induced by T. cruzi infection may be partially related to multiple endocrine changes involving the hypothalamus-pituitary axis and corresponding target endocrine glands.
Assuntos
Hormônio do Crescimento/metabolismo , Tolerância Imunológica/imunologia , Hipófise/metabolismo , Hipófise/parasitologia , Prolactina/metabolismo , Trypanosoma cruzi/imunologia , Animais , Células Cultivadas , Doença de Chagas/imunologia , Doença de Chagas/fisiopatologia , Regulação para Baixo/fisiologia , Sistema Endócrino/metabolismo , Sistema Endócrino/fisiopatologia , Matriz Extracelular/metabolismo , Hormônio do Crescimento/genética , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/parasitologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Laminina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Hipófise/fisiopatologia , Prolactina/genética , Fator de Transcrição Pit-1/metabolismoRESUMO
Highly sophisticated mechanisms confer on the immune system the capacity to respond with a certain degree of autonomy. However, the final outcome of an immune response depends on the interaction of the immune system with other systems. The immune and neuroendocrine systems have an intimate cross-communication that makes possible a satisfactory response to environmental changes. Part of this interaction occurs through cytokines and steroid hormones. The last step of this cross-talk is the molecular level. As a model of interaction, this review focuses on the gp130 cytokine family. These cytokines, as well as their receptors, are expressed in pituitary cells. They regulate hormone production as well as growth of pituitary cells. During acute or chronic inflammation or infection, systemic, hypothalamic and hypophyseal gp130 cytokines act on anterior pituitary cells, integrating the neuroendocrine-immune response. Disruptions of these pathways may lead not only to abnormal growth of pituitary cells but also to immune disorders, for which, based on recent findings, targeting these cytokines might be a novel therapeutic approach.
Assuntos
Receptor gp130 de Citocina/fisiologia , Citocinas/fisiologia , Hormônios/fisiologia , Neuroimunomodulação/fisiologia , Transdução de Sinais/imunologia , Animais , Humanos , Sistemas Neurossecretores/fisiologiaRESUMO
The anterior pituitary can develop benign tumors of different sizes, classified as micro- and macroadenomas, frequently associated with high levels of hormone production, leading to different associated syndromes like Cushing's disease, acromegaly or prolactinomas. Much work has been done in order to understand the signaling pathways and the factors and hormones involved in the pituitary tumorigenic process. In recent years, much evidence has been collected and it is now well documented that cytokines of the gp130 family, such as interleukin-6, that use gp130 as a common signaling protein stimulate not only the proliferation but also the hormone secretion of pituitary cells. Experiments in vivo have shown that the overexpression of the gp130 receptor resulted in pituitary abnormal growth. Moreover, it has been recently described that bone morphogenetic protein-4 (BMP-4), a member of the TGF-beta family, has a stimulatory role on lactosomatotropic cells promoting the development of prolactinomas but it has an inhibitory action on the corticotropic lineage. This inhibitory action prevents Cushing's disease progression. Furthermore, BMP-4 mediates the antiproliferative action of retinoic acid in these cells. The present review highlights the most recent work about gp130 and TGF-beta cytokine families and their role in pituitary tumorigenesis.
Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Receptor gp130 de Citocina/fisiologia , Citocinas/fisiologia , Hipófise/fisiologia , Animais , Proteína Morfogenética Óssea 4 , Humanos , Modelos Biológicos , Família Multigênica/fisiologiaRESUMO
Bone morphogenetic protein-4 (BMP-4), a member of the transforming growth factor-Beta(TGF-Beta) family, is overexpressed in different prolactinoma models and induces the development of these lineage adenomas. SMAD proteins activated by growth factors of the TGF-Beta and BMP family interact with estrogen receptors to stimulate the proliferation of prolactin and growth hormone-secreting cells. Furthermore, BMP-4 presents differential expression in normal and adenomatous corticotropes and inhibitory action on corticotropinoma cell proliferation. Moreover, BMP-4 mediates the antiproliferative action of retinoic acid in these cells. The present review highlights not only the crucial and opposite role of BMP-4 in the progression of pituitary adenomas but also that BMP-4 and retinoic acid interaction might serve as a potential new mechanism target for therapeutic approaches for Cushing disease.
Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Doenças da Hipófise/etiologia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Proteína Morfogenética Óssea 4 , Proteínas Morfogenéticas Ósseas/metabolismo , Expressão Gênica , Humanos , Modelos Biológicos , Neurônios/metabolismo , Hipófise/citologia , Hipófise/crescimento & desenvolvimento , Hipófise/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Tretinoína/farmacologiaRESUMO
Functional interactions between neuroendocrine and immune systems are mediated by similar ligands and receptors, which establish a bi-directional communication that is relevant for homeostasis. We investigated herein the hypothalamus-pituitary-adrenal (HPA) axis in mice acutely infected by Trypanosoma cruzi, the causative agent of Chagas' disease. Parasites were seen in the adrenal gland, whereas T. cruzi specific PCR gene amplification product was found in both adrenal and pituitary glands of infected mice. Histological and immunohistochemical analyses of pituitary and adrenal glands of infected animals revealed several alterations including vascular stasis, upregulation of the extracellular matrix proteins fibronectin and laminin, as well as T cell and macrophage infiltration. Functionally, we detected a decrease in CRH and an increase in corticosterone contents, in hypothalamus and serum respectively. In contrast, we did not find significant changes in the amounts of ACTH in sera of infected animals, whereas the serum levels of the glucocorticoid-stimulating cytokine, IL-6 (interleukin-6), were increased as compared to controls. When we analyzed the effects of T. cruzi in ACTH-producing AtT-20 cell line, infected cultures presented lower levels of ACTH and pro-opiomelanocortin production when compared to controls. In these cells we observed a strong phosphorylation of STAT-3, together with an increased synthesis of IL-6, suppressor of cytokine signaling 3 (SOCS-3) and inhibitor of activated STAT-3 (PIAS-3), which could explain the partial blockage of ACTH production. In conclusion, our data reveal that the HPA axis is altered during acute T. cruzi infection, suggesting direct and indirect influences of the parasite in the endocrine homeostasis.
Assuntos
Doença de Chagas/fisiopatologia , Sistema Hipotálamo-Hipofisário/microbiologia , Sistema Hipófise-Suprarrenal/microbiologia , Glândulas Suprarrenais/microbiologia , Glândulas Suprarrenais/fisiologia , Hormônio Adrenocorticotrópico/análise , Hormônio Adrenocorticotrópico/metabolismo , Animais , Corticosterona/análise , Corticosterona/metabolismo , Hormônio Liberador da Corticotropina/análise , Hormônio Liberador da Corticotropina/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Hipotálamo/microbiologia , Hipotálamo/fisiologia , Immunoblotting , Imuno-Histoquímica , Interleucina-6/análise , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Hipófise/microbiologia , Hipófise/fisiologia , Sistema Hipófise-Suprarrenal/metabolismo , Proteínas Inibidoras de STAT Ativados/análise , Proteínas Inibidoras de STAT Ativados/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/análise , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/análise , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Trypanosoma cruziRESUMO
The molecular mechanisms governing the pathogenesis of ACTH-secreting pituitary adenomas are still obscure. Furthermore, the pharmacological treatment of these tumors is limited. In this study, we report that bone morphogenetic protein-4 (BMP-4) is expressed in the corticotrophs of human normal adenohypophysis and its expression is reduced in corticotrophinomas obtained from Cushing's patients compared with the normal pituitary. BMP-4 treatment of AtT-20 mouse corticotrophinoma cells has an inhibitory effect on ACTH secretion and cell proliferation. AtT-20 cells stably transfected with a dominant-negative form of the BMP-4 signal cotransducer Smad-4 or the BMP-4 inhibitor noggin have increased tumorigenicity in nude mice, showing that BMP-4 has an inhibitory role on corticotroph tumorigenesis in vivo. Because the activation of the retinoic acid receptor has an inhibitory action on Cushing's disease progression, we analyzed the putative interaction of these two pathways. Indeed, retinoic acid induces both BMP-4 transcription and expression and its antiproliferative action is blocked in Smad-4dn- and noggin-transfected Att-20 cells that do not respond to BMP-4. Therefore, retinoic acid induces BMP-4, which participates in the antiproliferative effects of retinoic acid. This new mechanism is a potential target for therapeutic approaches for Cushing's disease.
Assuntos
Adenoma/patologia , Proteínas Morfogenéticas Ósseas/farmacologia , Proteínas Morfogenéticas Ósseas/fisiologia , Síndrome de Cushing/patologia , Neoplasias Hipofisárias/patologia , Tretinoína/farmacologia , Animais , Proteína Morfogenética Óssea 4 , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Camundongos , Hipófise/patologia , Hipófise/fisiologia , Valores de ReferênciaRESUMO
OBJECTIVE: gp130 cytokines are placed as auto-paracrine regulators of pituitary function, since they, as well as their receptors, have been shown to be expressed in and to act in normal and tumoral anterior pituitary cells. The objective of this work was to study their involvement in a model that shows the interaction between different cellular types that participate in a tumorigenic process. DESIGN: The dependence of a pituitary somatotrophic cell line (MtT/S) on a gp130 cytokine-producing folliculostellate (FS) cell line (TtT/GF) for tumorigenesis in vivo has been described. In order to study the participation of gp130 cytokines in the auto-paracrine stimulation of MtT/S growth, we generated MtT/S gp130 sense (gp130-S) and gp130 antisense (gp130-AS) clones stably transfected with pcDNA3/gp130 sense and pcDNA3/gp130 antisense vectors respectively. METHODS AND RESULTS: Functional characterization studies revealed that gp130-AS clones have an inhibited gp130 signalling, and proliferation studies showed that they have an impaired response to gp130 cytokines but respond normally to other independent stimuli. When injected into nude mice, MtT/S clones respond differently depending on cell number; at high concentrations MtT/S clones alone generated tumours equivalent in size to tumours derived from MtT/S plus TtT/GF cells. At low concentrations, MtT/S sense and control clones generated tumours of smaller size than tumours derived from these same clones plus TtT/GF cells, showing a dependence on FS cells. In both cases MtT/S gp130-AS clones had impaired tumour development. Furthermore, vessel density was significantly lower in tumours derived from gp130-AS plus TtT/GF cells. CONCLUSIONS: This study underlines the importance of gp130 cytokines in proliferation and establishes its role in auto-paracrine pituitary growth regulation.
Assuntos
Antígenos CD/metabolismo , Hormônio do Crescimento/metabolismo , Glicoproteínas de Membrana/metabolismo , Adeno-Hipófise/metabolismo , Neoplasias Hipofisárias/etiologia , Animais , Vasos Sanguíneos/patologia , Divisão Celular , Linhagem Celular , Receptor gp130 de Citocina , Camundongos , Camundongos Nus , Transplante de Neoplasias , Comunicação Parácrina , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/fisiopatologia , Ratos , TransfecçãoRESUMO
Nur77 and Nurr1 are critical for proopiomelanocortin (POMC) regulation by corticotrophin releasing hormone (CRH) in corticotrophs. We analyze the regulation and activity of Nur77 by interleukin (IL)-1 in AtT-20 corticotrophic cells and its consequences on POMC regulation. IL-1 induces Nur77 and not Nurr1 mRNA and shows an increased transcriptional activity on the NurRE site, an effect dependent of p38 protein kinase activity. A NurRE mutation abrogates POMC promoter transcription by IL-1 and a stable AtT-20 clone overexpressing a dominant negative form of Nur77 is unresponsive to IL-1-dependent POMC induction and adrenocorticotrophin (ACTH) secretion. These results demonstrate that Nur77 is essential for POMC stimulation by IL-1 in corticotrophs.