RESUMO
UNLABELLED: In spite of considerable evidence on the regulation of immunity by thyroid hormones, the impact of the thyroid status in tumor immunity is poorly understood. Here, we evaluated the antitumor immune responses evoked in mice with different thyroid status (euthyroid, hyperthyroid, and hypothyroid) that developed solid tumors or metastases after inoculation of syngeneic T lymphoma cells. Hyperthyroid mice showed increased tumor growth along with increased expression of cell cycle regulators compared to hypothyroid and control tumor-bearing mice. However, hypothyroid mice showed a higher frequency of metastases than the other groups. Hyperthyroid mice bearing tumors displayed a lower number of tumor-infiltrating T lymphocytes, lower percentage of functional IFN-γ-producing CD8(+) T cells, and higher percentage of CD19(+) B cells than euthyroid tumor-bearing mice. However, no differences were found in the distribution of lymphocyte subpopulations in tumor-draining lymph nodes (TDLNs) or spleens among different experimental groups. Interestingly, hypothyroid TDLN showed an increased percentage of regulatory T (Treg) cells, while hyperthyroid mice displayed increased number and activity of splenic NK cells, which frequency declined in spleens from hypothyroid mice. Moreover, a decreased number of splenic myeloid-derived suppressor cells (MDSCs) were found in tumor-bearing hyperthyroid mice as compared to hypothyroid or euthyroid mice. Additionally, hyperthyroid mice showed increased cytotoxic activity, which declined in hypothyroid mice. Thus, low levels of intratumoral cytotoxic activity would favor tumor local growth in hyperthyroid mice, while regional and systemic antitumor response may contribute to tumor dissemination in hypothyroid animals. Our results highlight the importance of monitoring the thyroid status in patients with T cell lymphomas. KEY MESSAGES: T cell lymphoma phenotype is paradoxically influenced by thyroid status. Hyperthyroidism favors tumor growth and hypothyroidism rises tumor dissemination. Thyroid status affects the distribution of immune cell types in the tumor milieu. Thyroid status also modifies the nature of local and systemic immune responses.
Assuntos
Imunomodulação , Linfoma de Células T/imunologia , Linfoma de Células T/metabolismo , Doenças da Glândula Tireoide/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hipertireoidismo/metabolismo , Hipotireoidismo/metabolismo , Contagem de Linfócitos , Linfoma de Células T/complicações , Linfoma de Células T/patologia , Camundongos , Metástase Neoplásica , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Doenças da Glândula Tireoide/complicações , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/farmacologia , Carga Tumoral , Microambiente Tumoral/imunologiaRESUMO
Thyroid hormones are important regulators of cell physiology, inducing cell proliferation, differentiation or apoptosis, depending on the cell type. Thyroid hormones induce proliferation in short-term T lymphocyte cultures. In this study, we assessed the effect of long-term thyroxine (T4) treatment on the balance of proliferation and apoptosis and the intermediate participants in T lymphoma cells. Treatment with T4 affected this balance from the fifth day of culture, inhibiting proliferation in a time-dependent manner. This effect was associated with apoptosis induction, as characterized through nuclear morphological changes, DNA fragmentation, and Annexin V-FITC/Propidium Iodide co-staining. In addition, increased iNOS gene and protein levels, and enzyme activity were observed. The generation of reactive oxygen species, depolarization of the mitochondrial membrane, and a reduction in glutathione levels were also observed. The imbalance between oxidants and antioxidants species is typically associated with the nitration of proteins, including PKCζ, an isoenzyme essential for lymphoma cell division and survival. Consistently, evidence of PKCζ nitration via proteasome degradation was also observed in this study. Taken together, these results suggest that the long-term culture of T lymphoma cells with T4 induces apoptosis through the increased production of oxidative species resulting from both augmented iNOS activity and the loss of mitochondrial function. These species induce the nitration of proteins involved in cell viability, promoting proteasome degradation. Furthermore, we discuss the impact of these results on the modulation of T lymphoma growth and the thyroid status in vivo.
Assuntos
Apoptose/efeitos dos fármacos , Linfoma de Células T/metabolismo , Mitocôndrias/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/genética , Proteína Quinase C/genética , Tiroxina/farmacologia , Animais , Anexina A5 , Linhagem Celular Tumoral , Proliferação de Células , Corantes , Fragmentação do DNA/efeitos dos fármacos , Regulação da Expressão Gênica , Glutationa/metabolismo , Linfoma de Células T/genética , Linfoma de Células T/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Nitratos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Propídio , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Quinase C/metabolismo , Proteólise/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Fatores de TempoRESUMO
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
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
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.