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1.
Endocr Relat Cancer ; 25(6): 665-676, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29622689

RESUMO

Increased levels of the proto-oncogene pituitary tumor-transforming gene 1 (PTTG) have been repeatedly reported in several human solid tumors, especially in endocrine-related tumors such as pituitary adenomas. Securin PTTG has a critical role in pituitary tumorigenesis. However, the cause of upregulation has not been found yet, despite analyses made at the gene, promoter and mRNA level that show that no mutations, epigenetic modifications or other mechanisms that deregulate its expression may explain its overexpression and action as an oncogene. We describe that high PTTG protein levels are induced by the RWD-containing sumoylation enhancer (RWDD3 or RSUME), a protein originally identified in the same pituitary tumor cell line in which PTTG was also cloned. We demonstrate that PTTG and RSUME have a positive expression correlation in human pituitary adenomas. RSUME increases PTTG protein in pituitary tumor cell lines, prolongs the half-life of PTTG protein and regulates the PTTG induction by estradiol. As a consequence, RSUME enhances PTTG transcription factor and securin activities. PTTG hyperactivity on the cell cycle resulted in recurrent and unequal divisions without cytokinesis, and the consequential appearance of aneuploidies and multinucleated cells in the tumor. RSUME knockdown diminishes securin PTTG and reduces its tumorigenic potential in a xenograft mouse model. Taken together, our findings show that PTTG high protein steady state levels account for PTTG tumor abundance and demonstrate a critical role of RSUME in this process in pituitary tumor cells.


Assuntos
Adenoma/metabolismo , Neoplasias Hipofisárias/metabolismo , Securina/metabolismo , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , Chlorocebus aethiops , Humanos , Masculino , Camundongos Nus , Estabilidade Proteica , Proto-Oncogene Mas , Ratos , Fatores de Transcrição/genética
2.
Cell Death Differ ; 23(10): 1579-91, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27177020

RESUMO

FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.


Assuntos
Receptores de Glucocorticoides/metabolismo , Sumoilação , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Células HEK293 , Proteínas de Choque Térmico HSP90/metabolismo , Resposta ao Choque Térmico , Humanos , Lisina/metabolismo , Camundongos Endogâmicos BALB C , Modelos Biológicos , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Transcrição Gênica
3.
Oncogene ; 34(37): 4855-66, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-25500545

RESUMO

Somatic mutations or loss of von Hippel-Lindau (pVHL) happen in the majority of VHL disease tumors, which present a constitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. Recently described mechanisms for pVHL modulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determine the molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role of RSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL and negatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF-1 and 2α ubiquitination and degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytoma and hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen-dependent degradation stability reporter assay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHL interaction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in which RSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2α, vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumor progression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function.


Assuntos
Genes Supressores de Tumor , Fatores de Transcrição/fisiologia , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Animais , Células COS , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Chlorocebus aethiops , Progressão da Doença , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor/fisiologia , Hemangioblastoma/genética , Hemangioblastoma/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Feocromocitoma/genética , Feocromocitoma/patologia , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia
4.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;38(10): 1487-1494, Oct. 2005.
Artigo em Inglês | LILACS | ID: lil-409270

RESUMO

The extracellular matrix is a three-dimensional network of proteins, glycosaminoglycans and other macromolecules. It has a structural support function as well as a role in cell adhesion, migration, proliferation, differentiation, and survival. The extracellular matrix conveys signals through membrane receptors called integrins and plays an important role in pituitary physiology and tumorigenesis. There is a differential expression of extracellular matrix components and integrins during the pituitary development in the embryo and during tumorigenesis in the adult. Different extracellular matrix components regulate adrenocorticotropin at the level of the proopiomelanocortin gene transcription. The extracellular matrix also controls the proliferation of adrenocorticotropin-secreting tumor cells. On the other hand, laminin regulates the production of prolactin. Laminin has a dynamic pattern of expression during prolactinoma development with lower levels in the early pituitary hyperplasia and a strong reduction in fully grown prolactinomas. Therefore, the expression of extracellular matrix components plays a role in pituitary tumorigenesis. On the other hand, the remodeling of the extracellular matrix affects pituitary cell proliferation. Matrix metalloproteinase activity is very high in all types of human pituitary adenomas. Matrix metalloproteinase secreted by pituitary cells can release growth factors from the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis.


Assuntos
Humanos , Adenoma/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Proteínas da Matriz Extracelular/fisiologia , Hormônios Hipofisários/metabolismo , Neoplasias Hipofisárias/metabolismo , Adenoma/etiologia , Adenoma/patologia , Hormônio Adrenocorticotrópico , Transformação Celular Neoplásica/patologia , Proteínas da Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Integrinas/metabolismo , Metaloproteinases da Matriz/metabolismo , Neoplasias Hipofisárias/etiologia , Neoplasias Hipofisárias/patologia , Prolactina
5.
Braz J Med Biol Res ; 38(10): 1487-94, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16172741

RESUMO

The extracellular matrix is a three-dimensional network of proteins, glycosaminoglycans and other macromolecules. It has a structural support function as well as a role in cell adhesion, migration, proliferation, differentiation, and survival. The extracellular matrix conveys signals through membrane receptors called integrins and plays an important role in pituitary physiology and tumorigenesis. There is a differential expression of extracellular matrix components and integrins during the pituitary development in the embryo and during tumorigenesis in the adult. Different extracellular matrix components regulate adrenocorticotropin at the level of the proopiomelanocortin gene transcription. The extracellular matrix also controls the proliferation of adrenocorticotropin-secreting tumor cells. On the other hand, laminin regulates the production of prolactin. Laminin has a dynamic pattern of expression during prolactinoma development with lower levels in the early pituitary hyperplasia and a strong reduction in fully grown prolactinomas. Therefore, the expression of extracellular matrix components plays a role in pituitary tumorigenesis. On the other hand, the remodeling of the extracellular matrix affects pituitary cell proliferation. Matrix metalloproteinase activity is very high in all types of human pituitary adenomas. Matrix metalloproteinase secreted by pituitary cells can release growth factors from the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis.


Assuntos
Adenoma/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Proteínas da Matriz Extracelular/fisiologia , Hormônios Hipofisários/metabolismo , Neoplasias Hipofisárias/metabolismo , Adenoma/etiologia , Adenoma/patologia , Hormônio Adrenocorticotrópico/metabolismo , Transformação Celular Neoplásica/patologia , Proteínas da Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , Humanos , Integrinas/metabolismo , Metaloproteinases da Matriz/metabolismo , Neoplasias Hipofisárias/etiologia , Neoplasias Hipofisárias/patologia , Prolactina/metabolismo
7.
Immunol Cell Biol ; 79(4): 385-94, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11488986

RESUMO

After antigenic stimulation the increase in cytokine levels constitutes a fundamental event in the host defense and mediates many processes such as inflammation, B- and T-cell growth and differentiation and activation of effector cells. Most of these processes depend on the cytokine-induced activation of transcription factors that modulate the expression of target genes. Cytokines induce a rise in glucocorticoid levels, which are instrumental in controlling immune-cytokine overreactions. Because of their anti-inflammatory and immunosuppressive actions, glucocorticoids are highly useful as therapeutic drugs in a range of diseases. The cross-talk between cytokine-induced transcription factors such as nuclear factor-kappaB, activating protein-1, cAMP responsive element binding protein and nuclear factor of activated T cells, and glucocorticoid receptors involves both genomic and non-genomic actions, and constitutes the mechanism by which glucocorticoid repressive effects on cytokine synthesis and action take place. These molecular interactions represent the key for the study of physiological compensatory actions of corticosteroids, the interactions of cytokines and glucocorticoids at their target cells, as well as the therapeutic benefits and side-effects of synthetic steroids. For this reason, we will focus on the molecular aspects of cytokine-glucocorticoid interactions, represented by the cross-coupling between cytokine-mediated transcription factors and glucocorticoid receptors.


Assuntos
Citocinas/metabolismo , Regulação da Expressão Gênica , Glucocorticoides/metabolismo , Fatores de Transcrição/metabolismo , Citocinas/imunologia , Glucocorticoides/imunologia , Humanos , Modelos Biológicos , Receptores de Glucocorticoides/metabolismo , Linfócitos T/fisiologia
8.
J Endocrinol ; 169(3): 539-47, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11375124

RESUMO

Two of the most potent cytokines regulating anterior pituitary cell function are leukemia inhibitory factor (LIF) and interleukin (IL)-6, which belong to the cytokine family using the common gp130 signal transducer. Recently, the expression and action of two other members of this family, IL-11 and ciliary neurotrophic factor (CNTF), on different cell lines has also been demonstrated. We studied the expression of the specific receptor subunits for CNTF in mammotropic, non-functioning and somatotropic tumors and the action of CNTF and IL-11 in the regulation of hormone secretion in these and normal pituitary cells. The mRNA for the alpha chain specific for the CNTF receptor was detected by Northern blot in tumors secreting prolactin (PRL) and GH and in non-functioning tumors. We found that both IL-11 and CNTF exerted a similar stimulatory effect on GH mRNA expression in somatotropic monolayer cell cultures from acromegalic tumors, but these cytokines had no significant influence on GH secretion. CNTF stimulates prolactin secretion in lactotropic monolayer cell cultures from patients with prolactinoma. In monolayer cell cultures from normal rat anterior pituitary, IL-11 and CNTF had no significant effect on the release of either GH or PRL, or on GH mRNA. However, when the cells were cultured in aggregate cultures, in which the three-dimensional structure of the cells is reconstituted, both cytokines, in doses at which they had no effect on monolayer cultures, significantly stimulated both PRL and GH secretion. These data show that IL-11 and CNTF may act as regulatory factors in anterior pituitary cells, in which the three-dimensional structure of the gland is of critical importance.


Assuntos
Adenoma/metabolismo , Fator Neurotrófico Ciliar/farmacologia , Interleucina-11/farmacologia , Adeno-Hipófise/efeitos dos fármacos , Neoplasias Hipofisárias/metabolismo , Animais , Agregação Celular , Técnicas de Cultura de Células , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento Humano/biossíntese , Hormônio do Crescimento Humano/genética , Humanos , Masculino , Proteínas de Neoplasias/metabolismo , Adeno-Hipófise/citologia , Prolactina/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptor do Fator Neutrófico Ciliar/metabolismo , Células Tumorais Cultivadas
9.
J Neuroimmunol ; 109(1): 23-9, 2000 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-10969177

RESUMO

We focus on how the IL-1 system, T-helper1 (Th1) or Th2 cytokines and glucocorticoids, converge to give a unified physiological response. Glucocorticoids inhibit IL-1 and IL-1 receptor antagonist (IL-1ra) expression, Th1 cytokines stimulate both and Th2 cytokines stimulate IL-1ra and inhibit IL-1. Thus, during the Th1 response there is a window for IL-1 inflammatory activity, absent during the Th2 response. We also study the interactions among glucocorticoid and cytokine transcriptional activity. Glucocorticoids inhibit cytokine-induced transcription factors (NFkB, AP1) and cytokines enhance glucocorticoid receptor (GR) transcriptional activity, thus reciprocally fine tuning immunological control mechanisms.


Assuntos
Glucocorticoides/farmacologia , Interleucina-1/biossíntese , Células Th1/fisiologia , Células Th2/fisiologia , Animais , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Proteína Antagonista do Receptor de Interleucina 1 , Sistema Hipófise-Suprarrenal/fisiologia , Sialoglicoproteínas/fisiologia , Transdução de Sinais , Transcrição Gênica
10.
Endocrinology ; 141(5): 1746-53, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10803585

RESUMO

Two of the most potent cytokines regulating anterior pituitary cell function are leukemia inhibitory factor and interleukin-6 (IL-6), which belong to the cytokine receptor family using the common gp130 signal transducer. We studied the actions of two other members of this family, IL-11 and ciliary neurotropic factor (CNTF), on folliculostellate (FS) cells (TtT/GF cell line) and lactosomatotropic cells (GH3 cell line). The messenger RNA (mRNA) for the alpha-chain specific for the IL-11 receptor (1.7 kb) and CNTF receptor (2 kb) are expressed on both cell types. In addition, we detected CNTF receptor mRNA in normal rat anterior pituitary cells. IL-11 (1.25-5 nM) dose dependently stimulated the proliferation of FS cells. CNTF, at doses from 0.4-2 nM, also significantly stimulated the growth of these cells. In addition, both cytokines significantly stimulated proliferation of lactosomatotropic GH3 cells, and CNTF stimulated hormone production (GH and PRL) at 24 h by these cells. At 16-72 h, IL-11 stimulates the secretion of the angiogenic factor vascular endothelial growth factor by FS cells. In addition, both GH3 and FS cells express CNTF mRNA. These data suggest that IL-11 and CNTF may act as growth and regulatory factors in anterior pituitary cells.


Assuntos
Fator Neurotrófico Ciliar/fisiologia , Interleucina-11/fisiologia , Lactação/fisiologia , Adeno-Hipófise/fisiologia , Receptor do Fator Neutrófico Ciliar/biossíntese , Receptores de Interleucina/biossíntese , Animais , Divisão Celular , Linhagem Celular , Fatores de Crescimento Endotelial/metabolismo , Feminino , Subunidade alfa de Receptor de Interleucina-11 , Linfocinas/metabolismo , Masculino , Adeno-Hipófise/citologia , Ratos , Ratos Sprague-Dawley , Receptor do Fator Neutrófico Ciliar/genética , Receptores de Interleucina/genética , Receptores de Interleucina-11 , Proteínas Recombinantes/farmacologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
11.
Ann N Y Acad Sci ; 917: 672-7, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11268396

RESUMO

The main communicators between the neuroendocrine and immune systems are cytokines and hormones. We studied the molecular interaction between immune activators (cytokines and T-cell receptors [TCRs]) and the glucocorticoid receptor (GR) in cells in which glucocorticoids play a key regulatory function: (1) cellular targets of TNF-induced cytotoxicity; (2) the pituitary gland; and (3) thymic cells. Cytokines (TNF-alpha and IL-1) increase glucocorticoid-induced transcriptional activity of the GR via the DNA-glucocorticoid response elements (GREs) in cells transfected with a glucocorticoid-inducible reporter plasmid. As a functional physiological correlate, priming of fibroblastic cells with a low dose of TNF significantly increases the sensitivity to glucocorticoid inhibition of TNF-induced apoptosis (without involving NF-kappa B). Priming of AtT-20 mouse corticotrophs and Cushing pituitary cells with IL-1 increases the sensitivity to glucocorticoid inhibition of CRH-induced ACTH/POMC expression. In thymocytes, activation of the T-cell receptor counteracts the glucocorticoid-induced thymic apoptosis by downregulating the glucocorticoid action on GRE-driven apoptotic genes. Thus, cytokines and immune mediators prevent their own deleterious effects not only by stimulating glucocorticoid production, but also by modifying the sensitivity of the target cells for the glucocorticoid counter-regulatory action. The functional cross-talk at the molecular level between immune signals and glucocorticoids is essential to determine the biological response to both mediators and constitutes the ultimate level of interaction between the immune and neuroendocrine mediators.


Assuntos
Neuroimunomodulação , Receptor Cross-Talk/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Receptores de Citocinas/fisiologia , Receptores de Glucocorticoides/fisiologia , Transdução de Sinais , Animais , Citocinas/fisiologia , Humanos , Transcrição Gênica , Ativação Transcricional
12.
Neuroimmunomodulation ; 6(5): 367-72, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10474056

RESUMO

We have previously described the regulation of interleukin-1 receptor antagonist (IL-1ra) protein secretion and expression by IL-1, glucocorticoids and corticotropin-releasing hormone in monocytes in culture. In the present work, we analyze the direct effect of adrenocorticotropic hormone (ACTH) and beta-endorphin on the expression and secretion of IL-1ra by human monocytes in culture. ACTH exerted a dose-dependent inhibitory effect on lipopolysaccharide (LPS)-induced IL-1ra production and mRNA expression. Basal IL-1ra levels were not affected by treatment with any ACTH dose. In contrast, on human monocytes, beta-endorphin at concentrations as low as 10 pg/ml produced an increase of basal IL-1ra protein secretion and mRNA expression, this effect being reverted by pretreatment with naloxone. No effect of beta-endorphin was observed either in IL-1ra mRNA expression or protein secretion when cells were treated with LPS. The different effects of ACTH and beta-endorphin could account for their differential contribution to the inflammatory response: while ACTH contributes to the glucocorticoid overall control of the inflammatory response, beta-endorphin exerts an inhibitory tone on the resting IL-1 system. Because IL-1ra is essential in setting the level of monocyte and inflammatory response its differential regulation by the HPA axis hormones contributes to regulating the IL-1/inflammatory temporal response.


Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Pró-Opiomelanocortina/farmacologia , Receptores de Interleucina-1/antagonistas & inibidores , Sialoglicoproteínas/metabolismo , beta-Endorfina/farmacologia , Northern Blotting , Células Cultivadas , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Monócitos/efeitos dos fármacos , Monócitos/metabolismo
13.
Endocrinology ; 140(2): 690-7, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9927295

RESUMO

Functional interaction between the immune and neuroendocrine systems is mediated by humoral mediators, neurotransmitters, and cytokines, including TRH and PRL. We examined the role of neuroendocrine changes, particularly TRH and PRL, during the T cell-dependent immune response. After immunization of rats with sheep red blood cells (SRBC, a T cell-dependent antigen), an increase of hypothalamic TRH messenger RNA (mRNA) was observed at 4-24 h post immunization, in contrast to the decrease observed after treatment with lipopolysaccharide (LPS). During the above period, with SRBC, there was an increase in pituitary TRH receptor mRNA and plasma PRL levels but no changes in TSH and GH. Also, in contrast to the early corticosterone peak induced by LPS, the activation of the hypothalamic-pituitary-adrenocortical suppressive response appears in a late phase, 5-7 days after SRBC. Intracerebroventricular injection of antisense oligonucleotide complementary to rat TRH mRNA in conscious freely-moving rats immunized with SRBC resulted in a significant inhibition of specific antibody production and a concomitant inability to produce the peak in plasma PRL levels. These studies demonstrate, for the first time, that the T cell-dependent immune response is critically dependent on the early activation of TRH and PRL and that the neuroendocrine changes occurring during it are profoundly different from those occurring during the T cell-independent and inflammatory responses (LPS model).


Assuntos
Prolactina/fisiologia , Linfócitos T/imunologia , Hormônio Liberador de Tireotropina/fisiologia , Animais , Formação de Anticorpos/fisiologia , Eritrócitos/imunologia , Hormônio do Crescimento/sangue , Hipotálamo/metabolismo , Imunização , Injeções Intraventriculares , Masculino , Oligonucleotídeos/genética , Oligonucleotídeos/farmacologia , Prolactina/sangue , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Ovinos/sangue , Hormônio Liberador de Tireotropina/sangue , Hormônio Liberador de Tireotropina/genética
14.
Neuroimmunomodulation ; 6(1-2): 126-36, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-9876243

RESUMO

It is now largely established that the immune and neuroendocrine systems cross-talk by using similar ligands and receptors. In this context, the thymus-hypothalamus/pituitary axis can be regarded as a paradigm of connectivity in both normal and pathological conditions. For example, cytokines and thymic hormones modulate hypothalamic-pituitary functions: (a) interleukin (IL)-1 seems to upregulate the production of corticotropin-releasing factor and by adrenocorticotropin by hypothalamic neurons and pituitary cells, respectively; (b) thymulin enhances LH secretion. Conversely, a great deal of data strongly indicate that the hypothalamic-pituitary axis plays a role in the control of thymus physiology. Growth hormone (GH) for example, enhances thymulin secretion by thymic epithelial cells (TEC), both in vivo and in vitro, also increasing extracellular matrix-mediated TEC/thymocyte interactions. Additionally, gap junction-mediated cell coupling among TEC is upregulated by ACTH. In a second vein, it was shown that GH injections in aging mice increased total thymocyte numbers and the percentage of CD3-bearing cells, as well concanavalin-A mitogenic response and IL-6 production. In addition to mutual effects, thymus-pituitary similarities for cytokine and hormone production have been demonstrated. Cytokines such as IL-1, IL-2, IL-6, interferon-gamma, transforming growth factor-beta and others can be produced by hypothalamic and/or pituitary cells. Conversely, hormones including GH, PRL, LH, oxytocin, vasopressin and somatostatin can be produced intrathymically. Moreover, receptors for various cytokines and hormones are expressed in both the thymus and the hypothalamus/pituitary axis. Lastly, it is noteworthy that a thymus-pituitary connectivity can also be seen under pathological situations. In this regard, an altered HPA axis has been reported in AIDS, human falciparum malaria and murine rabies, that also show a severe thymic atrophy.


Assuntos
Sistema Hipotálamo-Hipofisário/fisiologia , Timo/fisiologia , Animais , Humanos , Modelos Biológicos , Comunicação Parácrina/fisiologia
15.
Front Neuroendocrinol ; 20(1): 71-95, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9882537

RESUMO

Recent evidence has demonstrated that cytokines and other growth factors act in the anterior pituitary gland. Using the traditional criteria employed to determine autocrine or paracrine functions our review shows that, in addition to their role as lymphocyte messengers, certain cytokines are autocrine or paracrine regulators of anterior pituitary function and growth. The cytokines known to regulate and/or be expressed in the anterior pituitary include the inflammatory cytokine family (IL-1 and its endogenous antagonist, IL-1ra; TNF-alpha, and IL-6), the Th1-cytokines (IL-2 and IFN-gamma), and other cytokines such as LIF, MIF, and TGF-beta. This review examines at the cellular, molecular, and physiological levels whether: (1) each cytokine alters some aspect of pituitary physiology; (2) receptors for the cytokine are expressed in the gland; and (3) the cytokine is produced in the anterior pituitary. Should physiological stimuli regulate pituitary cytokine production, this would constitute additional proof of their autocrine/paracrine role. In this context, we analyze in this review the current literature on the actions of cytokines known to regulate anterior pituitary hormone secretion, selecting the in vivo studies that support the direct action of the cytokine in the anterior pituitary. Further support for direct regulatory action is provided by in vitro studies, in explant cultures or pituitary cell lines. The cytokine receptors that have been demonstrated in the pituitary of several species are also discussed. The endogenous production of the homologous cytokines and the regulation of this expression are analyzed. The evidence indicating that cytokines also regulate the growth and proliferation of pituitary cells is reviewed. This action is particularly important since it suggests that intrinsically produced cytokines may play a role in the pathogenesis of pituitary adenomas. The complex cell to cell communication involved in the action of these factors is discussed.


Assuntos
Citocinas/fisiologia , Adeno-Hipófise/fisiopatologia , Animais , Comunicação Autócrina , Comunicação Celular , Divisão Celular/fisiologia , Células Cultivadas , Citocinas/classificação , Humanos , Comunicação Parácrina , Receptores de Citocinas/fisiologia
16.
Medicina (B Aires) ; 58(2): 189-93, 1998.
Artigo em Espanhol | MEDLINE | ID: mdl-9706254

RESUMO

A functional relationship between the neuroendocrine and immune systems has been clearly established. We examined the role of neuroendocrine changes, particularly thyrotropin-releasing hormone (TRH) and prolactin (PRL), during the T cell-dependent immune response. After immunization of rats with sheep red blood cells (SRBC, a T cell-dependent antigen) we observed: a) an increase of hypothalamic TRH mRNA at 4 to 24 h post-immunization (i.e.: SRBC vs saline: 4 h, 2.8x), in contrast to the decrease of TRH mRNA observed following treatment with LPS, a T-independent antigen (LPS vs saline: 4 h, 1.6x); b) an increase in pituitary TRH receptor mRNA and plasma PRL levels but no changes in thyroid-stimulating hormone and growth hormone plasma levels. Intracerebroventricular (icv) injection in conscious freely-moving rats of antisense oligonucleotide complementary to rat TRH mRNA resulted in: a) a significant inhibition of specific antibody production [ELISA 7 days: Ig(M/G): TRH sense vs TRH-antisense: 384 +/- 27 (n = 11) vs 193 +/- 22 (n = 11); p < 0.001]b) an inability to produce the peak in plasma PRL levels in rats immunized with SRBC [(12h post-immunization, TRH-sense vs TRH-antisense: 8.3 +/- 1.4 (n = 6) vs 2.2 +/- 0.5 (n = 6); p < 0.01]; c) a decrease in hypothalamic TRH mRNA (TRH-sense vs TRH-antisense: 12h, 1.7x). These studies demonstrate that the T-cell antigen needs an early activation of TRH and PRL for an adequate immune response, in contrast to the inhibition induced by a T-cell independent antigen.


Assuntos
Formação de Anticorpos/imunologia , Eritrócitos/imunologia , Sistema Imunitário/metabolismo , Sistemas Neurossecretores/metabolismo , Linfócitos T/imunologia , Hormônio Liberador de Tireotropina/sangue , Análise de Variância , Animais , Masculino , Oligonucleotídeos Antissenso/imunologia , Ratos , Ratos Wistar , Ovinos , Hormônio Liberador de Tireotropina/metabolismo
17.
Eur J Immunol ; 28(7): 2075-85, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9692875

RESUMO

Monocytes express IL-1 and IL-1 receptor antagonist (IL-1Ra) in response to lipopolysaccharide (LPS). IL-1 self-induction contributes to the increase in IL-1 following LPS stimulation. LPS-stimulated IL-1 and IL-1Ra production are inhibited by glucocorticoids. In the present work we examined the regulation of IL-1Ra by Th1 cytokine IFN-gamma, Th2 cytokine IL-4, glucocorticoids and IL-1 in human monocytes. We demonstrate that IL-1 contributes to LPS-induced IL-1 Ra expression as shown by IL-1 blockade in LPS-stimulated monocytes using a specific anti-IL-1beta antibody or recombinant IL-1Ra. Glucocorticoids inhibited IL-1beta-stimulated IL-1Ra mRNA expression and protein production. Glucocorticoids inhibited both IL-1-mediated and non-mediated LPS stimulation of IL-1Ra expression. Both IFN-gamma and IL-4 reversed the inhibitory effect of glucocorticoids on IL-1Ra expression and secretion. The effect of IFN-gamma was blocked by pretreatment of monocytes with an anti-IL-1beta blocking antibody, whereas the effect of IL-4 could not be blocked, demonstrating that IFN-gamma acts through a mechanism dependent on endogenous IL-1 production, whereas IL-4 acts through an IL-1-independent one. Consistent with this finding, IFN-gamma (but not IL-4) failed to reverse the inhibitory effect of glucocorticoids when stimulated by IL-1, and only IL-4 combined with IL-1 showed synergism resulting in an increase in IL-1 Ra production. The differential regulation and involvement of IL-1 in the expression of IL-1Ra by IFN-gamma, IL-4 and glucocorticoids sets the level of monocyte responsiveness during the Th1 or Th2 responses.


Assuntos
Glucocorticoides/farmacologia , Interferon gama/farmacologia , Interleucina-1/fisiologia , Interleucina-4/farmacologia , Monócitos/efeitos dos fármacos , Receptores de Interleucina-1/antagonistas & inibidores , Sialoglicoproteínas/antagonistas & inibidores , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Lipopolissacarídeos/farmacologia , RNA Mensageiro/análise , Sialoglicoproteínas/genética , Sialoglicoproteínas/metabolismo
18.
Ann N Y Acad Sci ; 840: 525-31, 1998 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-9629279

RESUMO

The pituitary gland expresses cytokines and their receptors. IL-2 receptor transcripts and protein products are co-localized in ACTH-, PRL-, and GH-producing cells (double immunofluorescence). IL-2 and IL-6 (1-1000 IU/ml) are involved in the autocrine/paracrine regulation of normal and tumor (GH3 mammosomatotroph cell line and adenoma cell cultures) anterior pituitary hormone-producing cell growth (cell number, DNA synthesis, c-fos mRNA expression and autoradiography combined with hormone staining). IL-1 regulates the growth of normal pituitary cells but does not act on GH3 cells. IL-1ra, which blocks this action, is expressed in tumoral pituitary (mainly GH- and ACTH-) cells. In ACTH- cells, IL-1 enhances glucocorticoid feedback, stimulating glucocorticoid response element transcriptional activity. Cytokines, through specific functional receptors, act as inter/auto-cellular factors that regulate not only the function but also the growth of anterior pituitary cells.


Assuntos
Citocinas/fisiologia , Adeno-Hipófise/crescimento & desenvolvimento , Adeno-Hipófise/fisiologia , Animais , Divisão Celular/fisiologia , Citocinas/metabolismo , Humanos , Interleucina-1/fisiologia , Adeno-Hipófise/citologia , Receptores de Interleucina-2/metabolismo
19.
Medicina (B Aires) ; 57(1): 75-80, 1997.
Artigo em Espanhol | MEDLINE | ID: mdl-9435375

RESUMO

We have previously shown that TNF-alpha and IL-1 may enhance the glucocorticoid (GC)-induced transcriptional activity of glucocorticoid receptor (GR) in different cell lines transfected with a reporter plasmid carrying GC response elements (GRE). In TNF-alpha and GC target cell lines, it was found that: 1) TNF-alpha enhanced GR number in L-929 cells, and 2) by transfection of these cells with a reporter plasmid carrying the GR promoter, that TNF-alpha-induced increase in GR is at the transcriptional level, 3) by electrophoretic mobility shift assay, using nuclear extracts of TNF-alpha (0.02 ng/ml) or TNF-alpha plus DEX (10 nM) stimulated L-929 cells, that cytokines can increase the binding of GR to GRE (45 min, 1.8 x), while the TNF-alpha-induced NFkB factor expression was not affected by GC. 4) As a biological correlate of this mechanism, priming of L-929 cells with TNF-alpha significantly increased (p < 0.001) the sensitivity to GC inhibition of TNF-alpha-induced apoptosis. The organism protects itself from an immune overreaction, not only via the HPA axis induction and an increase in GC by cytokines, but also enhancing the sensitivity to GC: by an increase in GR number, the binding to GRE and the transcription of GC target genes (e.g. TNF-alpha-induced apoptosis inhibitory genes). These mechanisms contribute to enhance the immunosuppressive and antiinflammatory GC activity, in order to maintain homeostasis.


Assuntos
Citocinas/fisiologia , Glucocorticoides/fisiologia , Receptores de Glucocorticoides/fisiologia , Apoptose , Homeostase , Interleucina-1/fisiologia , Transcrição Gênica , Transfecção , Fator de Necrose Tumoral alfa/fisiologia
20.
Mol Cell Endocrinol ; 124(1-2): 33-42, 1996 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-9027322

RESUMO

We have previously shown that interleukin-2 (IL-2) and IL-6, which are expressed in the anterior pituitary, affect anterior pituitary cell proliferation in normal rats and cell lines. Here we examined their effects on the c-fos expression by human anterior pituitary adenomas. Adenoma cells in culture do not express c-fos mRNA. In adenoma explants, however, c-fos expression was detected and was regulated by IL-2 or IL-6. In different tumors (ACTH-, PRL-, GH-secreting and non functioning adenomas), these interleukins had inhibitory or stimulatory effects but the kind of response does not seem to be associated to tumor type or size. Using blocking antibodies, we observed that intrinsic IL-2 and IL-6 regulate c-fos expression in the same way. Our data suggest that IL-2 and IL-6 are not only involved in the regulation of pituitary adenoma function but may also, given the role of c-fos in cell proliferation, be implicated in the development of human pituitary adenomas.


Assuntos
Adenoma/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes fos/genética , Interleucina-2/farmacologia , Interleucina-6/farmacologia , Neoplasias Hipofisárias/genética , Adenoma/patologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adeno-Hipófise , Neoplasias Hipofisárias/patologia , RNA Mensageiro/análise , RNA Neoplásico/análise , Células Tumorais Cultivadas
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