RESUMO
Immune challenge inhibits reproductive function and endocannabinoids (eCB) modulate sexual hormones. However, no studies have been performed to assess whether the eCB system mediates the inhibition of hormones that control reproduction as a result of immune system activation during systemic infections. For that reason, we evaluated the participation of the hypothalamic cannabinoid receptor CB1 on the hypothalamic-pituitary-gonadal (HPG) axis activity in rats submitted to immune challenge. Male adult rats were treated i.c.v. administration with a CB1 antagonist/inverse agonist (AM251) (500 ng/5 µL), followed by an i.p. injection of lipopolysaccharide (LPS) (5 mg/kg) 15 minutes later. Plasmatic, hypothalamic and adenohypophyseal pro-inflammatory cytokines, hormones and neuropeptides were assessed 90 or 180 minutes post-LPS. The plasma concentration of tumour necrosis factor α and adenohypophyseal mRNA expression of Tnfα and Il1ß increased 90 and 180 minutes post i.p. administration of LPS. However, cytokine mRNA expression in the hypothalamus increased only 180 minutes post-LPS, suggesting an inflammatory delay in this organ. CB1 receptor blockade with AM251 increased LPS inflammatory effects, particularly in the hypothalamus. LPS also inhibited the HPG axis by decreasing gonadotrophin-releasing hormone hypothalamic content and plasma levels of luteinising hormone and testosterone. These disruptor effects were accompanied by decreased hypothalamic Kiss1 mRNA expression and prostaglandin E2 content, as well as by increased gonadotrophin-inhibitory hormone (Rfrp3) mRNA expression. All these disruptive effects were prevented by the presence of AM251. In summary, our results suggest that, in male rats, eCB mediate immune challenge-inhibitory effects on reproductive axis at least partially via hypothalamic CB1 activation. In addition, this receptor also participates in homeostasis recovery by modulating the inflammatory process taking place after LPS administration.
Assuntos
Encefalite/imunologia , Sistema Hipotálamo-Hipofisário/imunologia , Receptor CB1 de Canabinoide/imunologia , Reprodução , Animais , Corticosterona/sangue , Citocinas/sangue , Dinoprostona/metabolismo , Encefalite/induzido quimicamente , Encefalite/metabolismo , Hormônios Hipotalâmicos/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Kisspeptinas/metabolismo , Lipopolissacarídeos , Hormônio Luteinizante/sangue , Masculino , Ratos Sprague-Dawley , Canais de Cátion TRPV/metabolismo , Testosterona/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
Much evidence has suggested that early life adversity can have a lasting effect on behavior. The aim of this study was to explore the impact of prenatal exposure to stress on cognition in adult life and how it impacts chronic stress situations. In addition, we investigated the participation of glucocorticoids, neurotrophins and cytokines in prenatal stress effects. For this purpose, pregnant mice were placed in a cylindrical restraint tube for 2h daily during the last week of pregnancy. Control pregnant females were left undisturbed during their entire pregnancy period. Object-in-place task results showed that adult female mice exposed to prenatal stress exhibited an impairment in spatial memory. However, in the alternation test this memory deficit was only found in prenatally stressed mice submitted to chronic stress. This alteration occurred in parallel with a decrease in BDNF, an increase in glucocorticoid receptors and an alteration of Th1/Th2 in the hippocampus. Interestingly, these changes were observed in peripheral lymph nodes as well. However, none of the mentioned changes were observed in adult male mice. These results indicate that lymphoid cells could be good candidates as peripheral markers of susceptibility to behavioral alterations associated with prenatal exposure to stress.
Assuntos
Citocinas/metabolismo , Linfócitos/metabolismo , Transtornos da Memória/etiologia , Fatores de Crescimento Neural/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/complicações , Animais , Encéfalo/metabolismo , Corticosterona/metabolismo , Citocinas/genética , Comportamento Exploratório , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/patologia , Camundongos , Fatores de Crescimento Neural/genética , Gravidez , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Reconhecimento Psicológico/fisiologiaRESUMO
Diabetes is associated with an increased risk of death from infectious disease. Hyperglycaemia has been identified as the main factor contributing to the development of diseases associated with diabetes mellitus. However, experimental evidence indicates individual susceptibility to develop complications of diabetes. In this context, the aim of this work was to study the immune response in a streptozotocin-induced type 1 diabetes in two mouse strains: BALB/cByJ and C57Bl/6J. The participation of hyperglycaemia and oxidative stress was also analysed. Diabetic BALB/cByJ mice showed a decrease in both the in-vivo and in-vitro immune responses, whereas diabetic C57Bl/6J mice had higher blood glucose but exhibited no impairment of the immune response. The influence of hyperglycaemia over the immune response was evaluated by preincubation of lymphocytes from normal mice in a high glucose-containing medium. T and B cells from BALB/cByJ mice showed a decrease in cell viability and mitogen-stimulated proliferation and an increase in apoptosis induction. An increase in oxidative stress was implicated in this deleterious effect. These parameters were not affected in the T and B lymphocytes from C57Bl/6J mice. In conclusion, BALB/cByJ mice were sensitive to the deleterious effect of hyperglycaemia, while C57BL/6J were resistant. Although an extrapolation of these results to clinical conditions must be handled with caution, these results highlight the need to contemplate the genetic background to establish models to study the deleterious effect of diabetes in order to understand phenotypical variations that are of clinical importance in the treatment of patients.
Assuntos
Diabetes Mellitus Experimental/imunologia , Hiperglicemia/imunologia , Estresse Oxidativo , Animais , Glicemia/análise , Diabetes Mellitus Experimental/metabolismo , Feminino , Glutationa/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , EstreptozocinaRESUMO
Stress, an important aspect of modern life, has long been associated with an altered homeostatic state. Little is known about the effect of the life stress on the outcome of diabetes mellitus, especially related to the higher risk of infections. Here, we evaluate the effects of chronic mild stress (CMS) exposure on the evolution of type I diabetes induced by streptozotocin administration in BALB/c mice. Exposure of diabetic mice to CMS resulted in a significant reduction of survival and a sustained increase in blood glucose values. Concerning the immune response, chronic stress had a differential effect in mice with diabetes with respect to controls, showing a marked decrease in both T- and B-cell proliferation. No correlation was found between splenic catecholamine or circulating corticosterone levels and the proliferative response. However, a significant negative correlation was found between glucose levels and concanavalin A- and lipopolysaccharide-stimulated proliferative responses of T and B cells. A positive correlation between blood glucose and splenic catecholamine concentrations was found in diabetic mice but not in controls subjected to CMS. Hence, the present report shows that diabetic mice show a worse performance in immune function after stress exposure, pointing to the importance of considering life stress as a risk factor for patients with diabetes.
Assuntos
Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/psicologia , Hormônios/fisiologia , Hiperglicemia/sangue , Estresse Psicológico/imunologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Glicemia/metabolismo , Catecolaminas/sangue , Células Cultivadas , Doença Crônica , Corticosterona/sangue , Feminino , Privação de Alimentos , Camundongos , Camundongos Endogâmicos BALB C , Mitógenos/farmacologia , Análise de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Privação de Água/fisiologiaRESUMO
This work shows a comparative study on the effects of chronic mild stress upon learning and memory and immunity, in BALB/c and C57BL/6 mice. Stressed BALB/c, but not C57Bl/6 mice, showed a poor learning performance, morphological alterations in the hippocampus with an increase in oxidative stress. A correlation between poor memory performance and the increase of the Th2/Th1 balance was found. Our results suggest that vulnerability to cognitive deficit associated with stress exposition could be related to a differential regulation of Th1/Th2 cytokine balance, suggesting a better learning performance for individuals that produce Th1 type cytokine after stress exposition.
Assuntos
Transtornos Cognitivos/imunologia , Transtornos Cognitivos/psicologia , Predisposição Genética para Doença , Estresse Psicológico/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Separação Celular , Transtornos Cognitivos/genética , Citocinas/imunologia , Citometria de Fluxo , Hipocampo/imunologia , Hipocampo/patologia , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Estresse Psicológico/genéticaRESUMO
Long-term exposure to stressful situations can affect the immune system. The T-cell response is an important component of anti-tumoral immunity. Hence, impairment of the immune function induced by a chronic stressor has been postulated to alter the immunosurveillance of tumors, thus leading to a worse neoplastic prognosis. Here, we show that chronic restraint stress affects T-cell mediated immunity in mice. This was evidenced by a decrease of mitogen-induced T-cell proliferation, a reduction in CD4(+)T lymphocyte number and a decrease of tumor necrosis factor-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) production in stressed mice. Additionally, mice subjected to chronic restraint stress displayed an enhancement of tumor growth in a syngeneic lymphoma model, i.e. an increase of tumor proliferation and a reduction of animal survival. Finally, stressed mice had a reduced specific cytotoxic response against these tumor cells. These results suggest that chronic exposure to stress promotes cancer establishment and subsequent progression, probably by depressing T-cell mediated immunity. The T-cell immunity impairment as well as the tumor progression enhancement emphasize the importance of the therapeutic management of stress to improve the prognosis of cancer patients.
Assuntos
Linfoma de Células T/imunologia , Estresse Psicológico/imunologia , Linfócitos T/imunologia , Animais , Comportamento Animal , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Feminino , Interferon gama/biossíntese , Células Matadoras Naturais/imunologia , Linfoma de Células T/patologia , Camundongos , Camundongos Endogâmicos BALB C , Restrição Física , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Diabetes is widely believed to predispose to serious infections. However, the mechanisms linking diabetes and immunosuppression are not well defined. One potential mediator of the altered defence mechanisms is hyperglycaemia. It has been identified as the main factor contributing to the development of diseases associated with diabetes mellitus. In this study we analyse the immune response in diabetes and the direct effect of hyperglycaemia on T and B lymphocyte reactivity. Diabetes induced an early decrease in IgG levels in the secondary response. However, both primary responses against a T-cell-dependent or independent antigen were affected after 6 months of diabetes induction. T- and B- cell proliferation was only decreased at this time. To gain insight into the potential mechanisms involved, we evaluated the influence of hyperglycaemia over the immune response. Pre-incubation of lymph node and spleen cells in a high glucose (HG) containing medium led to a significant time- and dose-dependent decrease in T- and B-cell proliferation. This effect was associated with the presence of HG-derived supernatants. Still viable cells after HG exposition were able to improve their proliferative response when cultured with the mitogen in a fresh standard medium. HG diminished cell viability, increased apoptosis and induced oxidative stress in lymphocytes. These results indicate that HG concentrations can directly affect lymphoid cell growth. An increase in oxidative stress would be implicated in this deleterious effect. The possibility that prolonged exposure to pathologically HG concentrations would result in the immunosuppressive state observed in diabetes is also discussed.
Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Hiperglicemia/imunologia , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta Imunológica , Feminino , Glucose/farmacologia , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Peroxidação de Lipídeos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Mitógenos/imunologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Chronic stress has been associated with impaired immune function. In this work we studied the effect of chronic mild stress (CMS) exposure on the early intracellular pathways involved in T cells after stimulation with mitogen. We found that mitogen stimulation of T lymphocytes from CMS-exposed mice resulted in a reduction of the intracellular [Ca2+] rise, an impairment of growth-promoting protein kinase C (PKC) activation, a lower NF-kappaB activation and an increase in the inhibitory cAMP-protein kinase A (PKA) pathway activity with respect to those found in control lymphocytes. However, T cell activation with the direct PKC activator phorbol 12-myristate 13-acetate plus calcium ionophore led to a similar proliferative response in both CMS and control lymphocytes, indicating that signals downstream of PKC would not be affected by stress. In summary, our results show that chronic stress induced an alteration in T cell early transduction signals that result in an impairment of the proliferative response.
Assuntos
Ativação Linfocitária , NF-kappa B/metabolismo , Proteína Quinase C/metabolismo , Estresse Fisiológico/imunologia , Linfócitos T/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Concanavalina A/farmacologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Ionóforos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Estresse Fisiológico/enzimologia , Linfócitos T/enzimologia , Linfócitos T/imunologia , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
The humoral response and the role of catecholamines and corticosterone were analyzed in a chronic mild stress (CMS) model of depression. Mice subjected for more than 6 weeks to CMS showed a significant decrease in T-cell dependent antibody production. However, T-cell independent humoral response was not altered. Serum corticosterone levels and splenic norepinephrine (NE) contents showed an early increase but they were not altered after prolonged CMS exposure. Nevertheless, hormonal inhibitory effect on T lymphocyte reactivity was higher in 6-week CMS mice compared to non-exposed animals. Thus, our results suggest that the impaired T-cell dependent humoral response in a CMS model of depression is neither related to changes in glucocorticoids nor in NE levels but is correlated with an increment of T-cell sensitivity to stress hormones. These findings would underlie the involvement of catecholamines and glucocorticoid lymphocyte receptors in the immune alterations observed in stress and depression.
Assuntos
Formação de Anticorpos/imunologia , Corticosterona/sangue , Depressão/imunologia , Estresse Psicológico/imunologia , Linfócitos T/imunologia , Análise de Variância , Animais , Antígenos/imunologia , Doença Crônica , Depressão/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Norepinefrina/metabolismo , Baço/metabolismo , Estresse Psicológico/metabolismo , Linfócitos T/metabolismoRESUMO
Previously we described a decrease in beta-adrenergic receptor expression in B lymphocytes as a consequence of in vivo alloimmunization. This decrease correlates with the highest response of alloantibody production by B cells. In the present report we examined the participation of intracellular signals elicited after alloimmune stimulation. We showed that in vitro stimulation of B cells with mitomycin C-treated allogenic cells induced a reduction in the number of beta-adrenoceptors. This downregulation correlated to changes in basal and in isoproterenol-stimulated intracellular cAMP levels. We found that calcium mobilization and protein kinase C activation triggered after direct allogenic stimulation and/or by the action of T cell-soluble factors induced the reduction in beta-adrenoceptor sites. These findings could be of interest to understand the neuroendocrine mechanisms involved in the regulation of B cell activation.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Regulação para Baixo/imunologia , Isoantígenos/imunologia , Ativação Linfocitária/imunologia , Receptores Adrenérgicos beta/biossíntese , Transdução de Sinais/imunologia , Animais , Linfócitos B/enzimologia , Cálcio/fisiologia , Sistema Livre de Células/imunologia , Meios de Cultivo Condicionados/farmacologia , Feminino , Isoanticorpos/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Proteína Quinase C/fisiologia , Receptores Adrenérgicos beta/metabolismo , Solubilidade , Linfócitos T/metabolismoRESUMO
beta-Adrenoceptor (betaAR) expression and function as well as its modulation via intracellular transduction signals, were analyzed on the T cell lymphoma BW5147. Independently to the kinetic of proliferation and relative to the number of receptors displayed in normal T lymphocytes, BW5147 cells displayed a decreased number of betaAR, uncoupled to adenylate cyclase, but coupled to protein kinase C stimulation. This last effect was impaired by a beta-antagonist and by blockers of the enzymatic pathways involved in T lymphocyte proliferation, inducing a recovery of betaAR sites. Down-regulation of betaAR would implicate the loss of a negative neuroimmune control mechanism for lymphocyte proliferation. The coupling of the remaining sites to a positive signal for cellular activation, would contribute to establish an hyperproliferative state.
Assuntos
Proteína Quinase C/metabolismo , Receptores Adrenérgicos beta/metabolismo , Linfócitos T/citologia , Linfócitos T/enzimologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Adenilil Ciclases/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/imunologia , Ativação Enzimática/imunologia , Inibidores Enzimáticos/farmacologia , Humanos , Indóis/farmacologia , Isoproterenol/farmacologia , Linfoma de Células T , Maleimidas/farmacologia , Neuroimunomodulação/imunologia , Proteína Quinase C/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Células Tumorais CultivadasRESUMO
The effect of fluoxetine on mitogen-induced B-cell proliferation was studied. In particular, we analyzed the influence of fluoxetine on the signal transduction pathways triggered after stimulation with lipopolysaccharide (LPS) and anti-immunoglobulin M antibodies (anti-IgM). We showed that fluoxetine had a dual effect on anti-IgM-stimulated B-cell proliferation: at optimal anti-IgM concentration, fluoxetine inhibited proliferation, whereas at suboptimal anti-IgM concentration, the drug enhanced proliferation. Fluoxetine exerted only an inhibitory effect on LPS-induced B-cell proliferation. Calcium influx seemed to be involved in these effects.
Assuntos
Anticorpos Anti-Idiotípicos/farmacologia , Linfócitos B/efeitos dos fármacos , Fluoxetina/farmacologia , Lipopolissacarídeos/farmacologia , Animais , Antidepressivos de Segunda Geração/farmacologia , Linfócitos B/citologia , Transporte Biológico , Cálcio/metabolismo , Divisão Celular/efeitos dos fármacos , Interações Medicamentosas , Feminino , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Biochemical signalling events coupled to the bradykinin B(2)-receptor subtype, related to nitric oxide and prostaglandin E(2) generation were studied in rat submandibular gland. Bradykinin stimulation of the B(2)-receptor triggered activation of phosphoinositide turnover, translocation of protein kinase C, stimulation of nitric oxide synthase activity, increased production of cGMP and release of prostaglandin E(2). Bradykinin stimulation of nitric oxide synthase and cGMP production was blunted by agents able to interfere with calcium/calmodulin and phospholipase C activities, while a protein kinase C inhibitor was able to stimulate bradykinin action. Moreover, a specific B(2)-bradykinin antagonist of the reversible nitric oxide synthase inhibitor abrogated the bradykinin stimulation of nitric oxide synthase activity, cGMP accumulation and prostaglandin E(2) generation. Furthermore, a specific inhibitor of phospholipase A(2) blocked the bradykinin-induced prostaglandin E(2) release. These results suggest that apart, from the direct effect of bradykinin as an inducer of vasopermeability, it also appears to be a vasoactive chemical mediator that triggers, through release of prostaglandin E(2), a feedback mechanism that induces a protective adaptation of the gland, modulating the course of inflammation.
Assuntos
Bradicinina/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/biossíntese , Receptores da Bradicinina/metabolismo , Glândula Submandibular/metabolismo , Análise de Variância , Animais , Bradicinina/farmacologia , GMP Cíclico/biossíntese , Dinoprostona/biossíntese , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Masculino , Fosfatidilinositóis/metabolismo , Proteína Quinase C/metabolismo , Ratos , Ratos Wistar , Receptor B2 da Bradicinina , Receptores da Bradicinina/agonistas , Transdução de Sinais/fisiologia , Estatísticas não Paramétricas , Glândula Submandibular/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
1. The aim of the present work was to determine hypoxia-induced modifications in the cascade of intracellular events coupled to muscarinic acetylcholine receptor (mAChR) activation in brain. For this purpose, enzymatic activities were measured on normoxically incubated frontal cortical slices from mice exposed to hypobaric hypoxia for 72 hr. 2. We found that hypoxia induced alterations in several cerebral enzymatic basal activities: it increased nitric oxide synthase (NOS), but it decreased both membrane protein kinase C (PKC) and phospholipase C activities. 3. The mAChR agonist carbachol was found to increase phosphoinositide hydrolysis to greater values in hypoxic tissues than those found in normoxic conditions. Furthermore, a greater translocation of PKC in response to carbachol was observed in hypoxic tissues than in normoxic ones. 4. Besides, carbachol induced a drastic reduction of NOS activity in hypoxic brains, at concentrations that stimulated this enzyme activity in normoxic preparations. In the latter, inhibition is obtained only with high concentrations of the cholinergic muscarinic agonist. 5. These results pointed to a carbachol-mediated mAChR hyperactivity induced by hypoxic insult. 6. The possibility that these effects would account for a compensatory mechanism to diminish NOS hyperactivity, probably protecting for NO neurotoxic action in hypoxic brain, is also discussed.
Assuntos
Lobo Frontal/fisiologia , Hipóxia Encefálica/fisiopatologia , Fenilcarbamatos , Receptores Muscarínicos/fisiologia , Transdução de Sinais/fisiologia , Pressão do Ar , Animais , Atropina/farmacologia , Carbacol/farmacologia , Carbamatos/farmacologia , Quelantes/farmacologia , Agonistas Colinérgicos/farmacologia , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Inibidores Enzimáticos/farmacologia , Lobo Frontal/citologia , Camundongos , Camundongos Endogâmicos , Antagonistas Muscarínicos/farmacologia , Neurônios/química , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Fosfatidilinositóis/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Proteína Quinase C/metabolismo , Receptor Cross-Talk/fisiologia , ômega-N-Metilarginina/farmacologiaRESUMO
Among the many examples of neuroendocrine-immune system interactions the relationship between the thyroid axis and the immune function has yet to be clearly established. Here we studied the influence of thyroid hormones on the course of an alloimmune response. Murine T(3) and T(4) levels were found to be increased a few days after the immunization of mice with allogeneic lymphoid cells. Besides in vivo treatment with T(4) was shown to increase alloantibody titers during the early stages of alloimmunization and to enforce lymphoid proliferation in vitro in a mixed lymphocyte reaction. Conversely, lowering thyroid hormone seric levels by propylthiouracil treatment, negatively modulates the humoral and cellular alloimmune responses. The evidence here points to the existence of a bidirectional communication between both systems. The possibility that the antigenic challenge would increase the thyroid gland activity thus leading to a positive modulatory action upon the immune response is also discussed.
Assuntos
Sistema Imunitário/fisiologia , Sistemas Neurossecretores/imunologia , Glândula Tireoide/imunologia , Animais , Feminino , Isoanticorpos/biossíntese , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
Muscarinic receptors play an important role in secretory and vasodilator responses in rat salivary glands. Nitric oxide synthase (NOS) appears to be one of the multiple effectors coupled to muscarinic receptors in both submandibular and sublingual glands although some differences have been found depending on the gland studied. First, submandibular glands had a lower basal activity of nitric oxide synthase than sublingual glands and the concentration-response curve for carbachol was bell-shaped in the former but not in sublingual glands. Second, cGMP levels displayed a similar profile to that observed for NOS activity in both glands. Third, protein kinase C also coupled to muscarinic receptor activation in the glands might have a regulatory effect on nitric oxide production since its activity was higher in basal conditions in submandibular than sublingual glands and it also increased in the presence of the agonist at a concentration that inhibited NOS activity in submandibular glands. The effects appear to be partly related to the expression of a minor population of M(1) receptors in submandibular glands absent in sublingual as determined in binding and signaling experiments with the muscarinic receptor antagonist pirenzepine.
Assuntos
Óxido Nítrico Sintase/metabolismo , Receptores Muscarínicos/fisiologia , Glândulas Salivares/metabolismo , Animais , Ativação Enzimática/fisiologia , Fosfatidilinositóis/fisiologia , Proteína Quinase C/metabolismo , Ratos , Transdução de Sinais/fisiologiaRESUMO
The aim of the present work was to analyze the effect of chronic stress on thyroid axis and its influence on the immune response. For this purpose a murine model of chronic stress was developed to evaluate and to correlate thyroid hormone levels with humoral alloimmune response. Results show a reduction in serum levels of thyroid hormones, specially a significant decrease in serum levels of triiodotyronine (T3) in stressed animals. On the other hand, alloimmunization was not able to induce an early increment in T3 and thyroxine (T4) levels as it was previously reported in normal animals. In addition, lower titers of alloantibodies were obtained in animals under stress conditions as compared to normal mice. The sustitutive T4 treatment in stressed animals increased significantly alloantibody production as well as the early increment in thyroid hormones after antigenic challenge. These findings suggest that chronic stress induces an alteration of the function of thyroid axis that alters the immune response.
Assuntos
Formação de Anticorpos , Estresse Fisiológico/imunologia , Hormônios Tireóideos/fisiologia , Animais , Doença Crônica , Feminino , Isoanticorpos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Tri-Iodotironina/fisiologiaRESUMO
The induction of intracellular signals coupled to alpha1-adrenoceptor by haloperidol, were studied in rat cerebral frontal cortex. The neuroleptic exerts a biphasic effect on nitric oxide synthase (NOS), inhibiting the enzymatic activity at low concentrations (10(-9) M), while higher concentrations (10(-5) M) increased it. Protein kinase C (PKC) and phosphoinositol turnover (PIs) were involved in these actions, as haloperidol induced PKC translocation at low concentrations, and increased PIs turnover at high concentrations. All the effects of haloperidol were blocked by the alpha-adrenoceptor antagonist prazosin and the phospholipase C (PLC) inhibitor NCDC. The possibility that a cross-talk between both enzymatic pathways depending on the neuroleptic concentration used in rat cerebral frontal cortex, is also discussed.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 1 , Lobo Frontal/metabolismo , Haloperidol/farmacologia , Transdução de Sinais , Antagonistas de Receptores Adrenérgicos alfa 1 , Animais , Técnicas de Cultura , Lobo Frontal/efeitos dos fármacos , Fosfatos de Inositol/metabolismo , Líquido Intracelular/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Proteína Quinase C/metabolismo , RatosRESUMO
In this work, we studied the effect of fluoxetine on human T-lymphocyte proliferation using optimal and suboptimal concanavalin A concentrations. In particular, we analyzed the influence of fluoxetine on the kinases that are involved in intracellular signalling after stimulation with mitogens. We found that fluoxetine promoted the Ca2+ -mediated proteolysis of protein kinase C (PKC) and increased cyclic-AMP (cAMP) levels, thereby impairing lymphocyte proliferation, when optimal concanavalin A concentrations were used. In contrast, when suboptimal concanavalin A concentrations were used, fluoxetine only increased PKC translocation, without modifying cAMP levels, leading to T-cell proliferation. According to our results, fluoxetine has a dual effect on T-cell proliferation by modulating the PKC and protein kinase A pathways. This mechanism is thought to be mediated through Ca2+ mobilization.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , AMP Cíclico/fisiologia , Fluoxetina/farmacologia , Proteína Quinase C/fisiologia , Linfócitos T/efeitos dos fármacos , Adulto , Calcimicina/farmacologia , Cálcio/metabolismo , Divisão Celular/efeitos dos fármacos , Concanavalina A/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Ionóforos/farmacologia , Linfócitos T/citologia , Linfócitos T/enzimologiaRESUMO
The present study was undertaken to analyse the effect of fluoxetine upon murine T-lymphocyte proliferation. We found that fluoxetine exerted a dual effect, which depended on the degree of lymphocyte activation: at mitogenic concentration (2 microg/mL) of concavalin A (Con A), we observed an inhibitory effect on cellular proliferation, whereas, on submitogenic Con A concentration (1 microg/mL), fluoxetine stimulated the cellular response. Given these facts, we studied PKC activation and calcium mobilisation in both stimulatory and inhibitory effects of fluoxetine on T-cell proliferation. We observed that fluoxetine increased PKC translocation obtained with 1 microg/mL Con A concentration, whereas PKC was degraded when 2 microg/mL was used. This mechanism is thought to be mediated by calcium mobilisation. According to our results, fluoxetine seemed to modulate calcium influx, which, in turn, would influence PKC translocation, modulating the immune response.