RESUMO
Zinc and iron are crucial mineral components of human diet, because their deficiency leads to several disorders, including alterations of the immune function. It has been demonstrated, in both humans and rodents, that a diminished number of lymphoid cells and a loss of lymphocyte activity accompany deprivation of these essential minerals. The aim of this work was to analyze if iron and/or zinc imbalances regulate lymphocyte activity and the intracellular signals involved in the effect. Mice from the BALB/c strain were fed with iron- and/or zinc-deficient or mineral-supplemented diets, according to the American Institute of Nutrition Rodent Diets. Levels of iron and zinc were assessed in blood, liver, or bone samples. Selective mitogen stimulation of T- and B-lymphocytes were performed. We found a diminished proliferative response in T- and B-lymphocytes from zinc- and/or iron-deficient animals with respect to controls. These effects were related to decreased mitogen-induced translocation of protein kinase C (PKC) activity to cell membranes on both cell types from all animals fed with deficient diets. Our results demonstrate that iron and zinc deficiencies affect both T- and B-lymphocyte function by PKC-dependent mechanisms.
Assuntos
Linfócitos B/imunologia , Deficiências de Ferro , Proteína Quinase C/fisiologia , Linfócitos T/imunologia , Zinco/deficiência , Animais , Proliferação de Células/efeitos dos fármacos , Concanavalina A/farmacologia , Feminino , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Fito-Hemaglutininas/farmacologia , Mitógenos de Phytolacca americana/farmacologiaRESUMO
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
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
OBJECTIVE: Cardiac tissue from chagasic mice was studied to evaluate the expression and biological activity of beta-adrenoceptors in association with circulating beta-adrenoceptor-related autoantibodies. METHODS: BALB/c inbred mice that were either treated or not treated with atenolol (2.5 mg/kg) and infected or not infected with 1 x 10(4) trypomastigotes (CA-1 strain) were sacrificed weekly up to week nine. Morphological, binding and contractility studies were performed on the four different groups of animals. The effect of their serum antibodies was also assayed in binding and contractility studies on normal heart preparations. RESULTS: Hearts from chagasic myocarditis mice showed a beta-adrenoceptor-related dysfunction, with a decrease in heart contractility, impaired response to exogenous beta-adrenoceptor agonist and a significant reduction in beta-adrenergic binding sites. Those effects were maximum at eight-nine weeks post-infection and were improved by treating infected mice with atenolol. In addition, serum or IgG from chagasic myocarditis mice was capable of interacting with cardiac beta-adrenoceptors, reducing the number of binding sites and inhibiting the contractile response to exogenous norepinephrine. IgG effects that were observed in normal myocardium, were highest in sera from mice eight-nine weeks post-infection and correlate with the degree of myocarditis. Moreover, chagasic autoantibodies from infected mice recognized a peptide corresponding to the sequence of the second extracellular loop of the human beta 1-adrenoceptor. CONCLUSIONS: (1) The development of alterations in beta-adrenergic receptors, related to cardiac dysfunction, may be associated with the presence of circulating antibodies against these receptors and (2) it is possible that the chronic deposits of these autoantibodies in cardiac beta-adrenoceptors could lead to a progressive blockade with sympathetic denervation, a phenomenon that has been described in the course of chagasic myocarditis.
Assuntos
Autoanticorpos/sangue , Cardiomiopatia Chagásica/metabolismo , Miocárdio/imunologia , Receptores Adrenérgicos beta/imunologia , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/uso terapêutico , Análise de Variância , Animais , Atenolol/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/imunologia , Imunoglobulina G , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Contração Miocárdica , Fatores de TempoRESUMO
Here we demonstrate that T. cruzi antigen molecule SAPA (shed acute phase antigen) with neuraminidase-trans sialidase activity triggers down-regulation of T lymphocyte proliferation by interacting with T lymphocyte muscarinic acetylcholine receptors (mAChR). SAPA attachment to mAChR from Lyt 2.2+ T cells resulted in synthesis of cyclic GMP (cGMP) and secretion of PGE2, an immunoregulator effector substance. These T suppressor cell signals were blunted by atropine and by indomethacin. Cell sorter analysis showed that the interaction of SAPA with purified T cells, affected the ratio of L3T4+/Lyt 2.2+ T cells increasing the percentage of Lyt 2.2+ T cells, effect that was inhibited by the mAChR antagonist, atropine. The interaction between SAPA and mAChR from Lyt 2.2+ T cells may result, therefore, in the down-regulation of the host immune response as consequence of T suppressor/cytotoxic cells activation and PGE2 release as they were observed. These results support the theory of an immunosuppressive state that contribute to the chronic course of Chagas' disease.
Assuntos
Antígenos de Protozoários/fisiologia , Dinoprostona/metabolismo , Regulação para Baixo/fisiologia , Receptores Muscarínicos/fisiologia , Linfócitos T/fisiologia , Trypanosoma cruzi/imunologia , Animais , Atropina/farmacologia , Divisão Celular , Doença de Chagas/imunologia , Doença Crônica , Concanavalina A , GMP Cíclico/imunologia , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/imunologia , Regulação para Baixo/efeitos dos fármacos , Indometacina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
In this paper, we demonstrated that the production of PGE2 by CD8+ T lymphocytes through muscarinic cholinergic receptor (mAChR) activation of lymphocytes from mice acutely infected with nonlethal Trypanosoma cruzi CA-1 strain could enhance resistance to infection. Treatment in vivo with either atropine or cyclooxygenase inhibitors enhanced mortality rates and parasitemia of mice infected with T. cruzi CA-1 strain. The mechanism by which CD8+ T lymphocytes released PGE2 appears to involve the activation of the cells by circulating IgG present in mice infected with T. cruzi CA-1 strain. Binding of these antibodies to mAChR on CD8+ T lymphocytes triggered the release of large amounts of PGE2. The results point to a role of serum antibodies against mAChR in the protection of T. cruzi infection. The prostanoid acting as an immunomodulator contributed to the maintenance of the chronic course of experimental Chagas disease.
Assuntos
Adjuvantes Imunológicos/farmacologia , Linfócitos T CD8-Positivos/química , Doença de Chagas/imunologia , Dinoprostona/farmacologia , Receptores Colinérgicos/metabolismo , Receptores Muscarínicos/metabolismo , Animais , Atropina/farmacologia , Membrana Celular/parasitologia , Doença de Chagas/sangue , Dinoprostona/sangue , Imunidade Inata , Imunoglobulina G/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas Muscarínicos/farmacologia , Receptores Colinérgicos/imunologia , Receptores Muscarínicos/imunologia , Linfócitos T/metabolismo , Trypanosoma cruzi/isolamento & purificaçãoRESUMO
Circulating antibodies from human and murine chagasic sera are able to interact with myocardium, activating neurotransmitter receptors. Here, we studied the effects of a monoclonal antibody (MAb CAK20.12), which recognizes a 150 kilodalton antigen of Trypanosoma cruzi and reacts with normal human and murine striated muscles and with cardiac tissue. The MAb CAK20.12 binds to purified cardiac membranes and interferes with the binding of beta-adrenergic receptor radioligand ([125I]CYP) and muscarinic cholinergic receptor (mAChR) radioligand ([3H]QNB) in a noncompetitive way. As a consequence of this interaction, beta-adrenergic receptor and mAChR were activated, leading to increased intracellular levels of cyclic AMP as a result of beta-adrenergic receptor-coupled adenylate cyclase triggering. When its sympathetic action was abrogated, it also induced an mAChR-mediated increase in cyclic GMP. Furthermore, cardiac physiology was modified by MAb CAK20.12, as it was able to increase cardiac contractility through beta-adrenoceptor activation and to decrease atrial frequency as a result of mAChR activation. The fact that this MAb modulates and modifies the mechanical and biochemical activity of normal murine heart established an important basis for future research and understanding of how the host's humoral immune response acts on the course and development of the chronic chagasic myocardiopathy.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antiprotozoários/imunologia , Cardiomiopatia Chagásica/fisiopatologia , Coração/fisiologia , Trypanosoma cruzi/imunologia , Animais , Cardiomiopatia Chagásica/imunologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Humanos , Técnicas In Vitro , Iodocianopindolol , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas Muscarínicos/metabolismo , Contração Miocárdica , Miocárdio/imunologia , Miocárdio/metabolismo , Pindolol/análogos & derivados , Pindolol/metabolismo , Quinuclidinil Benzilato/metabolismoRESUMO
The expression of beta-adrenergic receptors on murine lymphocytes stimulated with concanavalin A was studied. A decrease in beta-adrenoceptor number on T lymphocytes and a diminished response to specific agonist stimulation at the peak of proliferation was found. The blockade of cell proliferation by tyrosine kinases or protein kinase C inhibitors reversed the decrease in beta-adrenoceptor number. PMA plus ionophore or interleukin-2 but not PMA alone were able to induce beta-adrenoceptor down-regulation accompanying cellular proliferation. These results showed that the intracellular signals triggered during lymphocyte activation are involved in beta-adrenoceptor down-regulation and it would represent the loss of a mechanism that exerts negative neuroimmune control of cellular proliferation.
Assuntos
Ativação Linfocitária/fisiologia , Receptores Adrenérgicos beta/metabolismo , Sulfonamidas , Linfócitos T/imunologia , Linfócitos T/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina , Animais , Calcimicina/farmacologia , Concanavalina A/farmacologia , AMP Cíclico/metabolismo , Regulação para Baixo , Genisteína , Técnicas In Vitro , Interleucina-2/metabolismo , Líquido Intracelular/metabolismo , Isoflavonas/farmacologia , Isoquinolinas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Neuroimunomodulação , Piperazinas/farmacologia , Inibidores de Proteínas Quinases , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores Adrenérgicos beta/imunologia , Transdução de Sinais , Linfócitos T/efeitos dos fármacosRESUMO
PGE2 involvement in experimental Trypanosoma cruzi infection depends on the lethal capacity of the parasite subpopulation used. Mice acutely infected with non-lethal K98 displayed an enhancement in PGE2 serum levels during the acute period, while those infected with lethal T. cruzi subpopulations (RA or K98-2) showed levels not different from normal mice. The enhancement detected in K98 group could be related both to an increased number of CD8+ T cell number and to enhanced PGE2 release per cell by CD8+; values of PGE2 release by adherent cells were not altered in this group. Treatment with cyclooxygenase inhibitors enhanced mortality rates of mice infected with K98, and administration of 16,16-dimethyl PGE2 (dPGE) reversed this effect. However, mice infected with RA did not reduce their mortality rates by administration of diverse doses of dPGE. These findings suggest that PGE2 could play a role in resistance in mice infected with K98.
Assuntos
Doença de Chagas/metabolismo , Dinoprostona/fisiologia , 16,16-Dimetilprostaglandina E2/farmacologia , Animais , Aspirina/farmacologia , Adesão Celular , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Dinoprostona/biossíntese , Dinoprostona/sangue , Indometacina/farmacologia , Contagem de Leucócitos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Linfócitos T/metabolismo , Trypanosoma cruzi/patogenicidadeRESUMO
beta adrenergic receptors (R) on murine lymphocytes stimulated with concanavalin A (Con A) and tumor lymphoid cell line (BW5147) were characterized by beta radioligand binding of 125Icyanopindolol (125I-CYP). The functionality was also assesses by hormone-dependent changes in cyclic 3', 5', adenosine monophosphate (cAMP) levels on intact cell. Both types of cells displayed a reduced number of beta adrenergic receptors by 125I-CYP specific binding. However BW5147 cell line were unable to respond to beta agonist stimulation meanwhile the response of lymphocytes stimulated with Con A was lower than normal lymphocytes. Despite this difference both kind of cells displayed an increase in cAMP production induced by Prostaglandin E1 (PGE1). It can be concluded that functional beta R are absent in BW5147 cell line. The possible implication of alternative transmission pathway and neuroendocrine control in tumor lymphoid cells is discussed.