RESUMO
PURPOSE: We have previously shown that domperidone-induced short-term hyperprolactinemia reduces the lung's allergic inflammatory response in an ovalbumin antigenic challenge model. Since purinergic receptor P2X7R activity leads to proinflammatory cytokine release and is possibly related to the pathogenesis of allergic respiratory conditions, the present study was designed to investigate a possible involvement of purinergic and prolactin receptors in this phenomenon. METHODS: To induce hyperprolactinemia, domperidone was injected intraperitoneally in rats at a dose of 5.1 mg × kg-1 per day for 5 days. P2X7 expression was evaluated by lung immunohistochemistry while prolactin receptor expression in bronchoalveolar lavage leukocytes was analyzed through flow cytometry. RESULTS: Previous reports demonstrated that rats subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, especially granulocytes. Here, it is revealed that hyperprolactinemia promotes an increased expression of prolactin receptors in granulocytes. Also, increased expression of purinergic P2X7R observed in allergic animals was significantly reduced by hyperprolactinemia. CONCLUSIONS: Both purinergic and prolactin receptor expression changes occur during the anti-asthmatic effect of hyperprolactinemia.
Assuntos
Asma/metabolismo , Hiperprolactinemia/metabolismo , Pulmão/metabolismo , Receptores Purinérgicos P2X7/biossíntese , Animais , Asma/induzido quimicamente , Asma/imunologia , Expressão Gênica , Hiperprolactinemia/imunologia , Contagem de Leucócitos/tendências , Pulmão/imunologia , Masculino , Ovalbumina/toxicidade , Ratos , Ratos Wistar , Receptores Purinérgicos P2X7/genética , Fatores de TempoRESUMO
Prolactin, a 23-kDa peptide hormone, is produced by the anterior pituitary gland and extrapituitary sites including the immune cells. Prolactin (PRL) participates in innate and adaptive immune response. PRL stimulates the immune cells by binding to receptor (PRL-R). Binding of PRL to its receptor activates the Janus kinase-signal transducer (JAK-STAT). Activation of these cascades results in endpoints such as immunoestimulator and immunosupressor action. Prolactin belongs to the network of immune-neuroendocrine interaction. Hyperprolactinemia has been found in patients with systemic lupus erythematosus (SLE), and new evidence has confirmed a significant correlation between serum PRL levels and disease activity. PRL participates in activation of SLE during pregnancy and in pathogenesis of lupus nephritis, neuropsychiatric, serosal, hematologic, articular, and cutaneous involvement. Hyperprolactinemia was associated with increase IgG concentrations, anti-DNA antibodies, immune complex, glomerulonephritis, and accelerated mortality in murine lupus. Bromocriptine, a dopamine analog that suppresses PRL secretion, was associated with decreased lupus activity, prolonged lifespan, and restoration of immune competence in experimental model. In clinical trials, bromocriptine and derivative drugs showed beneficial therapeutic effect in treating human lupus, including pregnancy. Taken together, clinical and experimental results leave little doubt that PRL indeed contributes to the pathogenesis and clinical expression of SLE.
Assuntos
Bromocriptina/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Hiperprolactinemia/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Complicações na Gravidez/imunologia , Prolactina/metabolismo , Imunidade Adaptativa , Animais , Anticorpos Antinucleares/sangue , Modelos Animais de Doenças , Feminino , Humanos , Hiperprolactinemia/tratamento farmacológico , Hiperprolactinemia/epidemiologia , Imunidade Inata , Imunocompetência , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/epidemiologia , Nefrite Lúpica/tratamento farmacológico , Camundongos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Prolactina/imunologia , Receptores da Prolactina/metabolismoRESUMO
We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1ß and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1ß expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny.
Assuntos
Adiposidade , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/etiologia , Resistência à Insulina , Lactação , Óleo de Semente do Linho/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Dislipidemias/imunologia , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Hiperprolactinemia/etiologia , Hiperprolactinemia/imunologia , Hiperprolactinemia/metabolismo , Hiperprolactinemia/patologia , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Leptina/sangue , Masculino , PPAR gama/metabolismo , Distribuição Aleatória , Ratos Wistar , Fatores Sexuais , Gordura Subcutânea/imunologia , Gordura Subcutânea/metabolismo , Gordura Subcutânea/patologiaRESUMO
AIMS: Prolactin is a major immunomodulator. The present study evaluated the effects of short-term hyperprolactinemia induced by domperidone before ovalbumin antigenic challenge on the lung's allergic inflammatory response. MAIN METHODS: To induce hyperprolactinemia, domperidone was injected in rats at a dose of 5.1mg·kg(-1) per day, i.p., for 5days from 10th to 14th day after OVA immunization. Total and differential leukocyte counts from bronchoalveolar lavage (BAL), femoral marrow lavage (FML), and blood were analyzed. The percentages of mucus and collagen production were evaluated. Levels of corticosterone and prolactin in serum, interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor α (TNF-α) in lung explants supernatants were measured and interferon gamma (IFN-γ) in bronchiolar lavage cells suspensions (BAL) was measured. KEY FINDINGS: The rats that were subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, cellularity decrease in femoral marrow lavage fluid, a lower percentage of mucus, and an increase in lung IL-4, IL-6, IL-10, TNF-α and IFN-γ expression. SIGNIFICANCE: Hyperprolactinemia induced before antigenic challenge decreased allergic lung inflammation. These data suggest that prolactin may play a role in the pathophysiology of asthma. The present study demonstrates a prospective beneficial side effect of domperidone for asthmatic patients.
Assuntos
Asma/imunologia , Hiperprolactinemia/imunologia , Pulmão/imunologia , Animais , Asma/sangue , Asma/induzido quimicamente , Asma/patologia , Citocinas/sangue , Citocinas/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperprolactinemia/sangue , Hiperprolactinemia/induzido quimicamente , Hiperprolactinemia/patologia , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Prolactina/toxicidade , Ratos , Ratos Wistar , Fatores de TempoRESUMO
OBJECTIVE: To establish whether there is a relationship between hyperprolactinemia and primary thyroid disorders, focusing on patients with autoimmune features. MATERIALS AND METHODS: The medical records of 100 patients with hyperprolactinemia (HPRL) were retrospectively examined. Records of thyroid ultrasonography (USG), basal serum levels of thyroid stimulating hormone, circulating free thyroxine, free triiodothyronine, antithyroglobulin (anti-Tg), and antithyroperoxidase (anti-TPO) antibodies were analyzed. In 100 control subjects, matched by age and gender with HPRL patients, thyroid USG, thyroid function tests (TFTs), and autoantibody panel were obtained. RESULTS: The median PRL in patients was 93 ng/mL (range: 37-470). Twenty-five patients (25%) and 22 controls (22%) had positive anti-Tg and/or anti-TPO titers (P = 0.739). The median serum PRL was 98 (37-470) ng/mL in patients with positive thyroid autoantibodies, and 92 (40-470) ng/mL in patients who were negative (P = 0.975). Among the individuals with autoantibody positivity TFTs abnormalities were more frequent in HPRL patients (60%, out of 25 patients, 14 with subclinical hypothyroidism and one with hyperthyroidism) than in controls (9.1%, out of 22 patients, 2 with subclinical hyperthyroidism) (P < 0.001). Twenty-seven patients with HPRL and 31 controls had goiter (27 vs. 31%, P = 0.437). Forty-six patients (46%) and 50 (50%) controls had one or more of the features of thyroid disorder, which were goiter, positive thyroid autoantibody, and thyroid function abnormality (P = 0.888). CONCLUSION: HPRL may be associated with more severe thyroid dysfunction in patients with thyroid autoimmunity.
Assuntos
Autoimunidade/fisiologia , Hiperprolactinemia/imunologia , Prolactina/sangue , Glândula Tireoide/imunologia , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Autoantígenos/sangue , Estudos de Casos e Controles , Feminino , Bócio/diagnóstico , Humanos , Iodeto Peroxidase/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Testes de Função Tireóidea , Glândula Tireoide/diagnóstico por imagem , Tireoidite Autoimune/diagnóstico , Tireotropina/sangue , Tiroxina/sangue , Ultrassonografia , Adulto JovemRESUMO
Objective : To establish whether there is a relationship between hyperprolactinemia and primary thyroid disorders, focusing on patients with autoimmune features. Materials and methods : The medical records of 100 patients with hyperprolactinemia (HPRL) were retrospectively examined. Records of thyroid ultrasonography (USG), basal serum levels of thyroid stimulating hormone, circulating free thyroxine, free triiodothyronine, antithyroglobulin (anti-Tg), and antithyroperoxidase (anti-TPO) antibodies were analyzed. In 100 control subjects, matched by age and gender with HPRL patients, thyroid USG, thyroid function tests (TFTs), and autoantibody panel were obtained. Results : The median PRL in patients was 93 ng/mL (range: 37-470). Twenty-five patients (25%) and 22 controls (22%) had positive anti-Tg and/or anti-TPO titers (P = 0.739). The median serum PRL was 98 (37-470) ng/mL in patients with positive thyroid autoantibodies, and 92 (40-470) ng/mL in patients who were negative (P = 0.975). Among the individuals with autoantibody positivity TFTs abnormalities were more frequent in HPRL patients (60%, out of 25 patients, 14 with subclinical hypothyroidism and one with hyperthyroidism) than in controls (9.1%, out of 22 patients, 2 with subclinical hyperthyroidism) (P < 0.001). Twenty-seven patients with HPRL and 31 controls had goiter (27 vs. 31%, P = 0.437). Forty-six patients (46%) and 50 (50%) controls had one or more of the features of thyroid disorder, which were goiter, positive thyroid autoantibody, and thyroid function abnormality (P = 0.888). Conclusion : HPRL may be associated with more severe thyroid dysfunction in patients with thyroid autoimmunity. .
Objetivo : Verificar se existe uma relação entre a hiperprolactinemia e distúrbios primários da tireoide, focando em pacientes com características autoimunes. Materiais e métodos : Os prontuários de 100 pacientes com hiperprolactinemia (HPRL) foram examinados retrospectivamente. Foram analisados registros de ultrassonografia da tireoide (USG), níveis séricos basais de hormônio tireoestimulante, tiroxina livre, triiodotironina livre e anticorpos antitireoglobulina (anti-Tg) e antitireoperoxidase (anti-TPO). Foram obtidos de 100 controles, pareados por idade e sexo com pacientes com HPRL, USG, testes de função da tireoide (TFTs) e painel de autoanticorpos. Resultados : A média de PRL em pacientes foi de 93 ng/mL (variação: 37-470). Vinte e cinco pacientes (25%) e 22 controles (22%) foram positivos para títulos de anti-Tg e/ou anti-TPO (P = 0,739). A mediana de PRL sérica foi de 98 (37-470) ng/mL em pacientes positivos para autoanticorpos tiroidianos e 92 (40-470) ng/mL em pacientes negativos (P = 0,975). Entre os indivíduos positivos para autoanticorpos, as anormalidades da TFTs foram mais frequentes em pacientes HPRL (60%; de 25 pacientes, 14 com hipotireoidismo subclínico e um com hipertireoidismo) do que nos controles (9,1%; de 22 pacientes, 2 com hipertireoidismo subclínico) (P < 0,001). Vinte e sete pacientes com HPRL e 31 controles apresentavam bócio (27 contra 31%; P = 0,437). Quarenta e seis pacientes (46%) e 50 (50%) controles tiveram uma ou mais das características de problemas de tireoide, como bócio, autoanticorpos antitireoide e anormalidades da função tiroidiana (P = 0,888). Conclusão : A HPRL pode estar associada à disfunção da tireoide mais grave em pacientes com autoimunidade contra a tireoide. .
Assuntos
Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Autoimunidade/fisiologia , Hiperprolactinemia/imunologia , Prolactina/sangue , Glândula Tireoide/imunologia , Autoanticorpos/sangue , Autoantígenos/sangue , Estudos de Casos e Controles , Bócio/diagnóstico , Iodeto Peroxidase/imunologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Testes de Função Tireóidea , Glândula Tireoide , Tireoidite Autoimune/diagnóstico , Tireotropina/sangue , Tiroxina/sangueRESUMO
Prolactin (PRL) plays an important role in modulating the immune response. In B cells, PRL enhances antibody production, including antibodies with self-specificity. In this study, our aims were to determine the level of PRL receptor expression during bone-marrow B-cell development and to assess whether the presence of high PRL serum concentrations influences absolute numbers of developing populations and disease outcome in lupus-prone murine models. We observed that the PRL-receptor is expressed in early bone-marrow B-cell; the expression in lupus-prone mice, which had the highest level of expression in pro-B cells and immature cells, differed from that in wild-type mice. These expression levels did not significantly change in response to hyperprolactinemia; however, populations of pro-B and immature cells from lupus-prone strains showed a decrease in the absolute numbers of cells with high PRL-receptor expression in response to PRL. Because immature self-reactive B cells are constantly being eliminated, we assessed the expression of survival factor BIRC5, which is more highly expressed in both pro-B and immature B-cells in response to PRL and correlates with the onset of disease. These results identify an important role of PRL in the early stages of the B-cell maturation process: PRL may promote the survival of self-reactive clones.
Assuntos
Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Prolactina/metabolismo , Animais , Anticorpos Antinucleares/imunologia , Linfócitos B/metabolismo , Modelos Animais de Doenças , Feminino , Hiperprolactinemia/genética , Hiperprolactinemia/imunologia , Hiperprolactinemia/metabolismo , Imunofenotipagem , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Lúpus Eritematoso Sistêmico/genética , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos MRL lpr , Prolactina/sangue , Receptores da Prolactina/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , SurvivinaRESUMO
Fasting serum prolactin (PRL) levels in response to metoclopramide (MCP) and lymphocyte cytokine profiles was studied in patients given allografts and their donors. Thirty normoprolactinemic volunteers (12-59 years) were studied: group 1, 10 healthy men; group 2, 8 males and 2 females with various hematologic diseases; and group 3, 3 males and 7 females HLA-identical sibling donors: PRL and cytokines were measured. Four surviving recipients developed acute graft-versus-host disease (GVHD) (+), and six did not. Before transplant Fasting PRL concentrations were higher in 'future' GVHD(+) recipients than in their donors (P < 0.001). The opposite was seen in response to MCP (P = 0.01). Donors had a predominant T-helper type 1 (Th1) cytokine profile compared with recipients (P ≤ 0.02), and GVHD(+) recipients had a greater tumor necrosis factor (TNF) value than GVHD(-) (P = 0.05). After transplant On days +30 and +100, a mild sustained rise in fasting PRL levels occurred only in GVHD(+) recipients (P ≤ 0.05) simultaneously with a transient rise in Th1 cytokines. GVHD(-) recipients had no changes. Donors with a Th1 cytokine profile might be more prone to induce GVHD in their recipients, and a mild sustained rise in PRL concentrations after transplantation in recipients GVHD(+) might participate in the amelioration of the severity of GVHD.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Hiperprolactinemia/imunologia , Prolactina/imunologia , Doença Aguda , Adolescente , Adulto , Criança , Citocinas/imunologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/mortalidade , Antígenos HLA/imunologia , Humanos , Hiperprolactinemia/sangue , Hiperprolactinemia/mortalidade , Masculino , Pessoa de Meia-Idade , Prolactina/sangue , Índice de Gravidade de Doença , Irmãos , Taxa de Sobrevida , Equilíbrio Th1-Th2 , Doadores de Tecidos , Transplante HomólogoRESUMO
BACKGROUND: Prolactin is secreted from the pituitary gland and other organs, as well as by cells such as lymphocytes. Prolactin has an immunostimulatory effect and is associated with autoimmune diseases that are characterised by abnormal B cell activation, such as systemic lupus erythematosus (SLE). Our aim was to determine if different splenic B cell subsets express the prolactin receptor and if the presence of prolactin influences these B cell subsets and correlates with development of lupus. RESULTS: Using real-time PCR and flow cytometry, we found that different subsets of immature (transitional) and mature (follicular, marginal zone) B cells express different levels of the prolactin receptor and are differentially affected by hyperprolactinaemia. We found that transitional B cells express the prolactin receptor at higher levels compared to mature B cells in C57BL/6 mice and the lupus-prone MRL/lpr and MRL mouse strains. Transitional-1 (T1) B cells showed a higher level of prolactin receptor expression in both MRL/lpr and MRL mice compared to C57BL/6 mice. Hyperprolactinaemia was induced using metoclopramide, which resulted in the development of early symptoms of SLE. We found that T1 B cells are the main targets of prolactin and that prolactin augments the absolute number of T1 B cells, which reflects the finding that this B cell subpopulation expresses the highest level of the prolactin receptor. CONCLUSIONS: We found that all B cell subsets express the prolactin receptor but that transitional B cells showed the highest prolactin receptor expression levels. Hyperprolactinaemia in mice susceptible to lupus accelerated the disease and increased the absolute numbers of T1 and T3 B cells but not of mature B cells, suggesting a primary effect of prolactin on the early stages of B cell maturation in the spleen and a role of prolactin in B cell differentiation, contributing to SLE onset.
Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Receptores da Prolactina/metabolismo , Animais , Subpopulações de Linfócitos B/metabolismo , Feminino , Expressão Gênica , Centro Germinativo/metabolismo , Hiperprolactinemia/imunologia , Hiperprolactinemia/metabolismo , Lúpus Eritematoso Sistêmico/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Prolactina/administração & dosagem , Receptores da Prolactina/genética , Baço/citologia , Baço/metabolismoRESUMO
OBJECTIVES: The effects of short-term 5-day and long-term 30-day hyperprolactinemia induced by domperidone (1.7 mg/kg/day, s.c.) or ectopic pituitary graft on the acute inflammatory response induced by carrageenan were evaluated in male rats. Both models of hyperprolactinemia effectively increased serum prolactin (PRL) levels. METHODS: The volume in milliliters of inflammatory edema was measured by plethysmography 1, 2, 3, 4, 6, 8 and 24 h after carrageenan injection. The areas under the inflammatory time-response curves were compared. Additionally, the effects of hyperprolactinemia on body weight and serum corticosterone levels were evaluated. RESULTS: In both domperidone-treated and pituitary graft-implanted animals, short-term 5-day hyperprolactinemia increased the inflammatory response, while long-term 30-day hyperprolactinemia had anti-inflammatory effects. Body weight was not affected by either short- or long-term hyperprolactinemia. CONCLUSION: These results show that PRL has biphasic effects on the carrageenan-induced inflammatory response.
Assuntos
Edema/imunologia , Hiperprolactinemia/imunologia , Inflamação/imunologia , Neuroimunomodulação/fisiologia , Animais , Peso Corporal , Carragenina/toxicidade , Corticosterona/sangue , Edema/induzido quimicamente , Edema/metabolismo , Membro Posterior/patologia , Hiperprolactinemia/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Irritantes/toxicidade , Masculino , Pletismografia , Prolactina/sangue , Radioimunoensaio , Ratos , Ratos WistarRESUMO
BACKGROUND/AIM: Prolactin (PRL), a hormone produced by the pituitary gland, has multiple physiological functions, including immunoregulation. PRL can also be secreted in response to stressful stimuli. During stress, PRL has been suggested to oppose the immunosuppressive effects of inflammatory mediators. Therefore, the aim of the present study was to analyze the effects of short- and long-term hyperprolactinemia on the inflammatory response in rats subjected to acute or chronic cold stress. METHODS: Inflammatory edema was induced by carrageenan in male rats, and hyperprolactinemia was induced by injections of the dopamine receptor antagonist domperidone. The volume of inflammatory edema was measured by plethysmography after carrageenan injection. Additionally, the effects of hyperprolactinemia on body weight and serum corticosterone levels were evaluated. RESULTS AND CONCLUSION: Five days of domperidone-induced hyperprolactinemia increased the volume of inflammatory edema. No differences in serum corticosterone levels were observed between groups. No significant differences were found among 30 days domperidone-induced hyperprolactinemic animals subjected to acute stress and the inflammatory response observed in chronic hyperprolactinemic animals subjected to chronic stress. The results suggest that short-term hyperprolactinemia has pro-inflammatory effects. Because such an effect was not observed in long-term hyperprolactinemic animals, PRL-induced tolerance seems likely. We suggest that short-term hyperprolactinemia may act as a protective factor in rats subjected to acute stress. These data suggest that hyperprolactinemia and stress interact differentially according to the time period.
Assuntos
Hiperprolactinemia/imunologia , Hiperprolactinemia/patologia , Mediadores da Inflamação/administração & dosagem , Doença Aguda , Animais , Carragenina/administração & dosagem , Doença Crônica , Temperatura Baixa/efeitos adversos , Modelos Animais de Doenças , Domperidona/administração & dosagem , Edema/induzido quimicamente , Edema/imunologia , Edema/patologia , Hiperprolactinemia/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Masculino , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/imunologia , Prolactina/biossíntese , Prolactina/metabolismo , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Hyperprolactinemia (hyperPRL) has been associated with autoimmune rheumatic disorders and the presence of thyroid autoantibodies (tAb). The interrelation between these variables was the focus of this prospective study. METHODS: The study assessed six groups of individuals: 26 with systemic lupus erythematosus (SLE), 20 with rheumatoid arthritis (RA), 28 with tAb (tAb+), 14 with untreated hyperprolactinemia (hyperPRL), 10 with treated hyperPRL, and a control group (n = 28). Prolactin (PRL), free thyroxin, TSH, antibodies against thyroglobulin (TgAb), thyroid microsomal antigen (MsAb) and/or thyroid peroxidase (TPOAb) were determined in all patients. Those with hyperPRL had macroprolactin investigated by the polyethylene glycol (PEG) precipitation method. RESULTS: PRL (ng/mL) levels in the SLE, RA, and tAb+ groups were, respectively, 21.3 +/- 12.6, 11.5 +/- 7.4, and 12.5 +/- 8.6, and were significantly greater in the SLE group (p = 0.006) than in the controls (12.5 +/- 6.5) and in the other groups. Five patients had hyperPRL: three with SLE, one with RA, and one with tAb+. Macroprolactinemia was detected in three of the untreated hyperprolactinemic patients and in the hyperprolactinemic patient of the tAb+ group. Positivity for any of the tAb was 15% in the SLE, 15% in the RA, 57.1% in the untreated hyperPRL, 10% in the hyperPRL on treatment, and 3.6% in the control group. The presence of antibodies was significantly more frequent in the untreated hyperPRL group than in the control group (p = 0.001). CONCLUSIONS: The results indicate that the PRL level is higher in SLE patients and that in the presence of hyperPRL there is increased prevalence of antithyroid antibodies, evidencing the association of PRL and autoimmunity and pointing to the appropriateness of assessing and monitoring the progress of these markers in patients affected by these disorders.
Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Hiperprolactinemia/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Glândula Tireoide/imunologia , Adulto , Idoso , Artrite Reumatoide/sangue , Autoanticorpos/imunologia , Feminino , Humanos , Hiperprolactinemia/sangue , Iodeto Peroxidase/imunologia , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Prolactina/sangue , Estudos Prospectivos , Glândula Tireoide/metabolismoRESUMO
Prolactin (PRL) secretion by the pituitary is under the control of dopamine. Hyperprolactinemia has been found in patients with systemic lupus erythematosus (SLE) and seems to be associated with clinical activity. T-lymphocytes express PRL and those from SLE patients appear to secrete more PRL than controls. In this study, immuno-(RIA) and bio-(BIO) assayable PRL in both serum and culture media of peripheral blood mononuclear cells (PBMNC) from SLE and control subjects were evaluated in the basal state and in response to 10 mg oral administration of metoclopramide, a dopamine receptor antagonist. Prolactin size heterogeneity in serum and culture media and PRL gene transcription in PBMNC were also studied. Basal serum RIA-PRL, BIO-PRL and the BIO/RIA ratio were similar in both groups. The serum BIO-PRL response after metoclopramide was higher than RIA-PRL in SLE, and this increment was also greater than in control subjects. PBMNC from SLE subjects secreted and produced more BIO-PRL. After metoclopramide, secretion and production of PRL increased only in PBMNC from control women and not in those from SLE patients. Our results demonstrated an increased central dopaminergic tone in SLE and suggest that lymphocyte-derived PRL might contribute to alter the functional activity of the hypothalamic dopaminergic system in SLE attempting to maintain serum PRL within a physiological range.
Assuntos
Hiperprolactinemia/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Prolactina/metabolismo , Linfócitos T/metabolismo , Adulto , Western Blotting , Antagonistas de Dopamina/administração & dosagem , Feminino , Humanos , Hiperprolactinemia/imunologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Metoclopramida/administração & dosagem , Prolactina/imunologia , Linfócitos T/imunologiaRESUMO
Bacterial lipopolysaccharide (LPS) affects pituitary hormone secretion, including prolactin release, by inducing synthesis and release of cytokines such as tumor necrosis factor-alpha (TNF-alpha). Since prolactin is mainly under tonic inhibitory control of dopamine, we investigated the effect of LPS and TNF-alpha on the hypothalamic-pituitary dopaminergic system. LPS (100-250 microg/rat, i.p.) decreased serum prolactin levels after 1 or 3 h. Sulpiride, a dopaminergic antagonist, increased serum prolactin and blocked the inhibitory effect of LPS. LPS increased hypothalamic dopamine and DOPAC concentrations and the DOPAC/dopamine ratio both in mediobasal hypothalamus and the posterior pituitary. LPS also enhanced dopamine and DOPAC concentration in the anterior pituitary. LPS elevated plasma levels of epinephrine, norepinephrine and dopamine but it did not modify the concentration of epinephrine or norepinephrine in the tissues studied. The administration of TNF-alpha (i.c.v., 1 h, 100 ng/rat) decreased serum prolactin but did not affect plasma catecholamine levels. TNF-alpha did not modify the DOPAC/dopamine ratio in hypothalamus or posterior pituitary but increased dopamine and DOPAC concentrations in the anterior pituitary. Incubations of hypothalamic explants showed that TNF-alpha did not modify in vitro basal dopamine release and reduced K(+)-evoked dopamine release. On the contrary, incubations of posterior pituitaries showed that TNF-alpha significantly increased basal and K(+)-evoked dopamine release. These results indicate that LPS and TNF-alpha increase dopamine turnover in the hypothalamic-pituitary axis. This increase in dopaminergic activity could mediate the inhibitory effect of LPS and TNF-alpha on prolactin release. Furthermore, the increase in dopaminergic activity elicited by LPS could be mediated by an increase in hypothalamic TNF-alpha during endotoxemia.
Assuntos
Infecções Bacterianas/imunologia , Dopamina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Lipopolissacarídeos/imunologia , Prolactina/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Infecções Bacterianas/sangue , Dopamina/sangue , Epinefrina/sangue , Epinefrina/metabolismo , Hiperprolactinemia/imunologia , Hiperprolactinemia/microbiologia , Hiperprolactinemia/fisiopatologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Norepinefrina/sangue , Norepinefrina/metabolismo , Adeno-Hipófise/efeitos dos fármacos , Adeno-Hipófise/metabolismo , Neuro-Hipófise/efeitos dos fármacos , Neuro-Hipófise/metabolismo , Prolactina/sangue , Prolactina/efeitos dos fármacos , Ratos , Ratos Wistar , Voo Espacial , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Prolactin (PRL) is a versatile hormone that is produced by the anterior pituitary gland and various extrapituitary sites including immune cells. Furthermore, PRL has widespread influences on proliferation and differentiation of a variety of cells in the immune system and is, in effect, a cytokine. PRL-receptors (PRL-R) are distributed throughout the immune system and are included as members of the cytokine receptor superfamily. PRL-R signal transduction is mediated by a complex array of signaling molecules of which JAK2, Stat1 and Stat5 pathway have been well studied. In PRL-stimulated T cells, the transcription factor gene, interferon regulatory factor-1 provides a mechanism whereby PRL can regulate the immune response. The human PRL gene is situated on the short arm of chromosome 6 close to the major histocompatibility complex. Polymorphisms of the human PRL gene have implications for production of lymphocyte PRL in SLE. Mild and moderate hyperprolactinemia (HPRL) has been demonstrated in 20-30% of SLE patients and is associated with active disease. HPRL may have a role in lupus nephritis and central nervous system involvement of SLE patients. HPRL stimulated the production of autoantibodies. These evidences support the important role of PRL in autoimmunity and autoimmune diseases, mainly SLE.
Assuntos
Autoimunidade , Proteínas do Leite , Prolactina/imunologia , Proteínas Proto-Oncogênicas , Animais , Proteínas de Ligação a DNA/fisiologia , Humanos , Hiperprolactinemia/complicações , Hiperprolactinemia/imunologia , Imunogenética , Fator Regulador 1 de Interferon , Janus Quinase 2 , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/imunologia , Fosfoproteínas/fisiologia , Prolactina/genética , Prolactina/fisiologia , Proteínas Tirosina Quinases/fisiologia , Receptores da Prolactina/fisiologia , Fator de Transcrição STAT5 , Transdução de Sinais , Transativadores/fisiologiaRESUMO
In the last decade, evidence has accumulated to support the hypothesis that both mild and moderate elevations of serum prolactin (PRL) participate in the clinical expression and pathogenesis of systemic lupus erythematosus (SLE). Hyperprolactinemia (HPRL) has been found in 20-30% of patients with SLE. HPRL seems to be associated with clinical activity of SLE during pregnancy. Although the relationship between HPRL and active SLE in non-pregnant patients is controversial, recent clinical and experimental studies support the potential role of prolactin (PRL) as a promoter of clinical activity and severity of SLE. Mild elevations of serum PRL secondary to microadenoma could trigger the onset of SLE in a subset of patients. Elevated PRL and interleukin (IL)-6 have been found in the urine of patients with active lupus nephritis and in cerebrospinal fluid (CSF) of patients with active central nervous system (CNS) SLE. PRL may therefore participate in the pathogenesis of lupus nephritis and cerebritis, and the presence of PRL may reflect an abnormal communication between the immune system and the neuroendocrine system in active SLE. Lymphocytes from patients with active SLE produce increased amounts of PRL, and this extrapituitary PRL may participate in aberrant immune processes in SLE. There is exciting new evidence that HPRL in SLE may be explained by stimulation of pituitary PRL secretion by cytokines. In addition, defects in peptidergic modulators and dopamine metabolism have been described in patients with SLE. The interactions between PRL, cytoquines, autoantibodies and organ involvement suggest that PRL participates in local and generalized immune and inflammatory processes and acts as a bridge between the neuroendocrine and immune systems in SLE. Understanding the interactions between these systems in SLE will help us to understand and treat this important autoimmune disease.
Assuntos
Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/fisiopatologia , Prolactina/metabolismo , Autoanticorpos/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Humanos , Hiperprolactinemia/imunologia , Hiperprolactinemia/metabolismo , Hiperprolactinemia/fisiopatologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/fisiopatologia , Especificidade de Órgãos , Prolactina/imunologiaRESUMO
The aim of this study was to determine the frequency of anti-prolactin autoantibodies and the relationship among anti-prolactin autoantibodies, serum prolactin (PRL) levels and lupus activity in paediatric patients with systemic lupus erythematosus (SLE) using a transversal study. One-hundred and three consecutive paediatric SLE patients were tested for serum anti-PRL autoantibodies and PRL levels. Clinical disease activity was scored using the SLEDAI index. Anti-PRL autoantibodies were measured by means of gel filtration. The frequency of anti-PRL autoantibodies was 6.7% (7/103), on the basis of the amount of immunoreactive PRL eluted in molecular weight fraction corresponding to IgG (150 kDa). No anti-PRL autoantibodies were found in normoprolactinaemic patients. By contrast, 21.8% (7/32) hyperprolactinaemic patients (hPRL) had anti-PRL autoantibodies. There was a correlation between anti-PRL autoantibody and serum levels of PRL (r(s) = 0.98, P = 0.0001). Lupus activity was present in 64/103 (62.1%) patients, without a significant difference in the frequency of anti-PRL autoantibodies when compared to inactive lupus (7.8 vs 5.1%, P > 0.05). Higher levels of serum PRL were associated with lupus activity regardless of other variables (39.6% vs 17.9%, P = 0.05). Patients with anti-PRL autoantibodies had higher levels of serum PRL than those without anti-PRL autoantibody (41.85 vs 17.77 ng/ml, P = 0.01) and significantly different frequency of hPRL (100 vs 26%, r = 0.4531, P < 0.001). We have identified a subset of paediatric SLE patients with hPRL and anti-PRL autoantibodies. Anti-PRL autoantibodies were associated with hPRL state and antibody titres correlated positively with serum PRL levels. These data suggest that anti-PRL autoantibodies could be responsible for hPRL in a subset of SLE patients. An increase in serum PRL levels proved to be related to lupus activity, but there was no statistical relationship between anti-PRL autoantibodies and lupus activity.
Assuntos
Autoanticorpos/sangue , Hiperprolactinemia/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Prolactina/imunologia , Adolescente , Criança , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Prolactina/sangue , Índice de Gravidade de DoençaAssuntos
Hiperprolactinemia/imunologia , Hiperprolactinemia/fisiopatologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Uveíte/imunologia , Uveíte/fisiopatologia , Adulto , Feminino , Humanos , Hiperprolactinemia/sangue , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Prolactina/sangue , Estudos Retrospectivos , Uveíte/sangueRESUMO
We investigated patients with lupus erythematosus to detect the presence of hyperprolactinemia and to determine it's origin. From the seric specimens obtained in 225 patients with LES, we found 37 (14.5%) with hyperprolactinemia and they were trated with polyethylenglicol, in 11 of 37 patients (29.7%) had a high significance of prolactin precipitation (PRL). The test in gel filtration shown the big-big PRL (Molecular weight > 100 kDa) was the predominant form from PRL seric in these patients and no woman had clinic effects of hyperprolactinemia as galactorrhea and/or amenorrhea. The big-big PRL essence was due to an antibody, with it was found like a immune complex (Ig-PRL). This evidence suggest the patients with LES and hyperprolactinemia have a very high incidence of macroprolactinemia relationated to antibodies anti-PRL, and in spite of the hyperprolactinemia not have clinical effects like amenorrhea and/or galactorrhea, and it is other cause to explain the high incidence of hyperprolactinemia in patients with LES.
Assuntos
Hiperprolactinemia/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Prolactina/imunologia , Autoanticorpos , Feminino , Humanos , MasculinoRESUMO
Encuestamos a pacientes con lupus eritematoso sistémico (LES) para detectar la presencia de macroprolactinemia y determinar su origen. De las muestras séricas obtenidas en 255 pacientes con LES en 37(14.5 por ciento) se encontró hiperprolactinemia y éstas fueron tratadas con polietilenglicol y en once de 37 pacientes (29.7 por ciento) hubo una proporción significativamente alta de precipitación prolactina (PRL). Los estudios en filtración en gel revelaron que la big-big PRL (peso molecular mayor de 100 kDa) fue la forma predominante de la PRL sérica en estos pacientes y en ninguna mujer se encontró manifestaciones clínicas de hiperprolactinemia como amenorrea y/o galactorrea. La naturaleza de la big-big PRL fue debida a un autoanticuerpo el cual se encontró como un complejo antígeno-anticuerpo (Ig-PRL). Estos datos sugieren que los pacientes con LES e hiperprolactinemia tiene una frecuencia muy alta de macroprolactinemia y que es debida a un autoanticuerpo anti-PRL, y que a pesar de la hiperprolactinemia no presentan las manifestaciones clínicas comunes a ella como amenorrea y/o galactorrea y ésta es una causa más que explica la alta frecuencia de hiperprolactinemia en pacientes con LES