RESUMEN
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.
Asunto(s)
Inmunomodulación , Linfoma de Células T/inmunología , Linfoma de Células T/metabolismo , Enfermedades de la Tiroides/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Hipertiroidismo/metabolismo , Hipotiroidismo/metabolismo , Recuento de Linfocitos , Linfoma de Células T/complicaciones , Linfoma de Células T/patología , Ratones , Metástasis de la Neoplasia , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Enfermedades de la Tiroides/complicaciones , Hormonas Tiroideas/metabolismo , Hormonas Tiroideas/farmacología , Carga Tumoral , Microambiente Tumoral/inmunologíaRESUMEN
We have shown in vitro that thyroid hormones (THs) regulate the balance between proliferation and apoptosis of T lymphoma cells. The effects of THs on tumor development have been studied, but the results are still controversial. Herein, we show the modulatory action of thyroid status on the in vivo growth of T lymphoma cells. For this purpose, euthyroid, hypothyroid, and hyperthyroid mice received inoculations of EL4 cells to allow the development of solid tumors. Tumors in the hyperthyroid animals exhibited a higher growth rate, as evidenced by the early appearance of palpable solid tumors and the increased tumor volume. These results are consistent with the rate of cell division determined by staining tumor cells with carboxyfluorescein succinimidyl ester. Additionally, hyperthyroid mice exhibited reduced survival. Hypothyroid mice did not differ significantly from the euthyroid controls with respect to these parameters. Additionally, only tumors from hyperthyroid animals had increased expression levels of proliferating cell nuclear antigen and active caspase 3. Differential expression of cell cycle regulatory proteins was also observed. The levels of cyclins D1 and D3 were augmented in the tumors of the hyperthyroid animals, whereas the cell cycle inhibitors p16/INK4A (CDKN2A) and p27/Kip1 (CDKN1B) and the tumor suppressor p53 (TRP53) were increased in hypothyroid mice. Intratumoral and peritumoral vasculogenesis was increased only in hyperthyroid mice. Therefore, we propose that the thyroid status modulates the in vivo growth of EL4 T lymphoma through the regulation of cyclin, cyclin-dependent kinase inhibitor, and tumor suppressor gene expression, as well as the stimulation of angiogenesis.
Asunto(s)
Hipertiroidismo/fisiopatología , Hipotiroidismo/fisiopatología , Linfoma de Células T/fisiopatología , Glándula Tiroides/fisiología , Animales , Apoptosis , Caspasa 3/biosíntesis , Proteínas de Ciclo Celular/biosíntesis , Línea Celular Tumoral , Proliferación Celular , Ciclina D1/biosíntesis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/biosíntesis , Femenino , Hipertiroidismo/complicaciones , Hipotiroidismo/complicaciones , Linfoma de Células T/patología , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Neovascularización Patológica , Antígeno Nuclear de Célula en Proliferación/biosíntesis , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
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.
Asunto(s)
Apoptosis/efectos de los fármacos , Linfoma de Células T/metabolismo , Mitocondrias/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/genética , Proteína Quinasa C/genética , Tiroxina/farmacología , Animales , Anexina A5 , Línea Celular Tumoral , Proliferación Celular , Colorantes , Fragmentación del ADN/efectos de los fármacos , Regulación de la Expresión Génica , Glutatión/metabolismo , Linfoma de Células T/genética , Linfoma de Células T/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Nitratos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Propidio , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteína Quinasa C/metabolismo , Proteolisis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Factores de TiempoRESUMEN
This paper reports the case of a 39-year-old woman who presented with symptoms of Eagle's Syndrome and an ossified stylohyoid ligament (SHL). Symptoms had developed immediately after trauma to the neck. No injury to the SHL was radiologically observable, but the causal relationship between the trauma and the occurrence of symptoms was evident. A new symptom of Eagle's Syndrome mimicking osteoathrosis of the temporomandibular joint was observed. The risk of misdiagnosis of temporomandibular disorders and the etiological role of neck trauma in Eagle's Syndrome are discussed.
Asunto(s)
Hueso Hioides/patología , Ligamentos/lesiones , Traumatismos del Cuello/complicaciones , Osificación Heterotópica/etiología , Hueso Temporal/patología , Adulto , Diagnóstico Diferencial , Dolor Facial/etiología , Femenino , Estudios de Seguimiento , Humanos , Osteoartritis/diagnóstico , Síndrome , Trastornos de la Articulación Temporomandibular/diagnósticoRESUMEN
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.
Asunto(s)
Linfocitos B/inmunología , Deficiencias de Hierro , Proteína Quinasa C/fisiología , Linfocitos T/inmunología , Zinc/deficiencia , Animales , Proliferación Celular/efectos de los fármacos , Concanavalina A/farmacología , Femenino , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Fitohemaglutininas/farmacología , Mitógenos de Phytolacca americana/farmacologíaRESUMEN
Apoptosis which is also a called programmed cell death plays an important role during development, homeostasis and in many diseases such as cancer. Apoptosis is a genetically encoded cell death program defined by characteristic morphological and biochemical features. It is well recognized as a distinct pathologic mechanism in tumours responding to anticancer therapies. Many genes play an important role in this process. We evaluated an expression of the tumour supressor gene p53 and proteins p21 and bcl-2 in non-small cell lung cancer. We examined resected tumour tissues from 30 patients who received neoadjuvant chemotherapy. As a control we assessed tissues from patients treated without chemotherapy. Histological slides of the resected tumours were evaluated by TUNEL, in situ hybridisation and with immunoperoxidase staining procedure. The results were documented by photography. We examined the level of extinction using cytophotometry. In conclusion, preoperative chemotherapy induces apoptosis in cancer cells. The level of p53 correlates with the acceleration of TUNEL reaction. The loss of bcl-2 expression correlated with an increased apoptotic cell death. There was an increased p21 protein expression in the examined cancer tissues after chemotherapy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Ciclinas/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteína p53 Supresora de Tumor/genética , Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/uso terapéutico , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Etopósido/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Humanos , Etiquetado Corte-Fin in Situ , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , ARN Mensajero/análisisRESUMEN
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.
Asunto(s)
Sistema Inmunológico/fisiología , Sistemas Neurosecretores/inmunología , Glándula Tiroides/inmunología , Animales , Femenino , Isoanticuerpos/biosíntesis , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
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.
Asunto(s)
Formación de Anticuerpos , Estrés Fisiológico/inmunología , Hormonas Tiroideas/fisiología , Animales , Enfermedad Crónica , Femenino , Isoanticuerpos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Triyodotironina/fisiologíaRESUMEN
It is well established that recanalization of the infarct-related artery has an important role in prognosis after myocardial infarction. Recanalization can be achieved by the use of thrombolytic agents or by percutaneous transluminal coronary angioplasty. This article reviews the role of primary coronary angioplasty in the management of acute myocardial infarction, and summarises current opinions and indications of its use.