María Laura Barreiro Arcos

Immune-endocrine interactions in autoimmune thyroid diseases.

Autoimmune thyroid diseases (AITD) are the most common organ-specific autoimmune disorders affecting approximately 5% of the overall population. An aberrant interaction between abnormal thyrocytes, abnormal antigen-presenting cells and abnormal T cells forms the basis for the atypical autoimmune reaction targeting thyroid antigens. It was proposed that nongenetic (environmental and hormonal) factors play a crucial etiological role in AITD development, through altering immune-endocrine interactions. The most outstanding fact is that in genetically predisposed individuals, the disruption of these neuroendocrine-immune interactions by environmental factors results in thyroid autoimmune dysfunction. These interactions are able to incline the balance between Th1-Th2 immune response toward one side, resulting in a Th1-cell-mediated autoimmune reaction with thyrocyte destruction and hypothyroidism in Hashimoto’s thyroiditis but to a hyperreactive Th2-mediated humoral response against TSH receptor with stimulatory antibodies leading to Graves’ disease hyperthyroidism. In this review the main mechanisms involved are summarized. In this sense, the participation of stress-mediated activation of the sympathoadrenal system and hypothalamic-pituitary-adrenal axis, the hormonal changes occurring during pregnancy and postpartum acting on antigen-presenting cells and influencing, in this way, the balance of the immune status are shown to participate in AITD etiology. The possibility that altered levels of thyroid hormones during the course of the AITD may alter immune function is also discussed.

Cooperative nongenomic and genomic actions on thyroid hormone mediated-modulation of T cell proliferation involve up-regulation of thyroid hormone receptor and inducible nitric oxide synthase expression.

Thyroid hormones (THs) exert a broad range of actions on development, growth, and cell differentiation by both genomic and nongenomic mechanisms. THs regulate lymphocyte function, but the participation of nongenomic actions is still unknown. Here the contribution of both genomic and nongenomic effects on TH‐induced division of T cells was studied by using free and noncell permeable THs coupled to agarose (TH‐ag). THs‐ag led to cell division, but to a lesser extent than free hormones. THs induced nongenomically the rapid translocation of protein kinase C (PKC) ζ isoform to cell membranes, extracellular‐signal‐regulated kinases (ERK1/2) phosphorylation and nuclear factor‐κB (NF‐κB) activation. The signaling cascade include sphingomielinases acting up‐stream the activation of PKCζ isoform, while ERK and NF‐κB are activated downstream this PKC isoenzyme. Both free and THs‐ag increased the protein and mRNA levels of TH nuclear receptor TRα1, while only free hormones incremented the inducible NOS gene and protein levels as well as a calcium independent NOS activity. Both effects were blunted by PKCζ inhibition. These results indicate that THs, by triggering a nongenomic signaling cascade that involves Smases‐mediated activation of PKCζ, lead to ERK 1/2 and NF‐κB activation and to the genomic increase of TRs and the inducible nitric oxide synthase protein and mRNA levels, improving T lymphocyte proliferation. These finding not only contribute to the understanding of the mechanisms involved in TH modulation of lymphocyte physiology, but would also point out for the first time the interplay between genomic and nongenomic TH actions in T cells. J. Cell. Physiol. 226: 3208–3218, 2011.

Involvement of Thyroid Hormones in the Alterations of T-Cell Immunity and Tumor Progression Induced by Chronic Stress

BACKGROUND Stress alters the neuroendocrine system, immunity, and cancer. Although the classic stress hormones are glucocorticoids and catecholamines, thyroid hormones have also been related to stress. We recently reported that chronic restraint stress impairs T-cell mediated immunity and enhances tumor growth in mice. METHODS To study the participation of these hormones on the stress-induced alterations of the immune function and lymphoma growth, mice were subjected to acute or chronic stress, with or without thyroxin supplementation. Hormone levels, immune status, and cancer progression were evaluated. RESULTS Differential endocrine alterations were observed in response to acute and chronic stress. Although corticosterone and noradrenaline levels were increased by acute stress, they were restored after prolonged exposure to the stressor. Instead, thyroid hormone levels were only reduced in chronically stressed animals in comparison with control subjects. Correlating, chronic but not acute stress impaired T-cell reactivity. Thyroxin replacement treatment of chronic restraint stress-exposed mice, which restored the euthyroid status, reversed the observed reduction of T-cell lymphoproliferative responses. Moreover, therapeutic thyroid replacement also reversed the alterations of lymphoma growth induced by chronic stress in syngeneic mice bearing tumors as well as Interleukin-2 production and specific cytotoxic response against tumor cells. Finally, we found that the isoforms theta and alpha of the protein kinase C are involved in these events. CONCLUSIONS These results show for the first time that thyroid hormones are important neuroendocrine regulators of tumor evolution, most probably acting through the modulation of T-cell mediated immunity affected by chronic stress.

Oral administration of fluoxetine alters the proliferation/apoptosis balance of lymphoma cells and up-regulates T cell immunity in tumor-bearing mice.

Antidepressants have a controversial role with regard to their influence on cancer and immunity. Recently, we showed that fluoxetine administration induces an enhancement of the T-cell mediated immunity in naïve mice, resulting in the inhibition of tumor growth. Here we studied the effects of fluoxetine on lymphoma proliferation/apoptosis and immunity in tumor bearing-mice. We found an increase of apoptotic cells (active Caspase-3(+)) and a decrease of proliferative cells (PCNA(+)) in tumors growing in fluoxetine-treated animals. In addition, differential gene expressions of cell cycle and death markers were observed. Cyclins D3, E and B were reduced in tumors from animals treated with fluoxetine, whereas the tumor suppressor p53 and the cell cycle inhibitors p15/INK4B, p16/INK4A and p27/Kip1 were increased. Besides, the expression of the antiapoptotic factor Bcl-2 and the proapoptotic factor Bad were lower and higher respectively in these animals. These changes were accompanied by increased IFN-γ and TNF-α levels as well as augmented circulating CD8(+) T lymphocytes in tumor-bearing mice treated with the antidepressant. Therefore, we propose that the up-regulation of T-cell mediated antitumor immunity may be contributing to the alterations of tumor cell proliferation and apoptosis thus resulting in the inhibition of tumor progression.

Different Mitogen-Mediated Beta-Adrenergic Receptor Modulation in Murine T Lymphocytes Depending on the Thyroid Status

Objective: The aim of this work was to analyze β-adrenergic receptor (βAR) regulation of T-lymphocyte proliferation in mice according to different thyroid hormone statuses. Methods: T cells from eu-, hypo- (by propylthiouracil treatment) and hyperthyroid (by thyroxine, T4 administration) mice were purified and specific radioligand binding assays were performed. The effects of the β-agonist isoproterenol (ISO) on intracellular levels of cyclic AMP (cAMP) were determined. Mitogen-induced T-cell proliferation was measured by [3H]-thymidine incorporation. Finally, protein kinase C (PKC) activity in cytosol and membrane fractions were determined using radiolabelled enzymatic substrates. Results: Adecrease or a non-significant increase in βAR number was found on T lymphocytes from hypo- and hyperthyroid mice compared to euthyroid controls. ISO stimulation of cAMP levels was lower in hypothyroid and higher in hyperthyroid T lymphocytes compared to controls. T-selective mitogen-induced proliferation was increased in T4-treated animals, but decreased in hypothyroid mice. During the peak of proliferation, downregulation of βAR was observed in all animals. However, a higher or a lower decrease was observed in hyper- and hypothyroid T cells, respectively. In parallel, a higher translocation of PKC activity was observed in hyperthyroid cells, and a lower one was found in hypothyroid lymphocytes with respect to controls. Conclusions: These results indicate that intracellular signals triggered by mitogen activation, namely PKC, would be related to differential βAR downregulation in T lymphocytes depending on the thyroid hormone status, contributing to the distinct proliferative responses found in hypo- or hyperthyroidism compared to the euthyroid state.

Effect of streptozotocin on reactive oxygen species and antioxidant enzyme secretion in rat submandibulary glands: A direct and an indirect relationship between enzyme activation and expression

The salivary glands are important exocrine and endocrine organs, whose role in oral health is well recognized. Also these glands contribute to the maintenance of systemic health. During diabetes an impairment of salivary glands is reported. In this work the oxidative stress produced after 10days of a single dose of streptozotocin administration in rats was observed in submandibulary glands. Under this condition a misbalance of the enzymes with antioxidant activity was observed in glands and in incubation medium, as well as in reactive oxygen species such as hydrogen peroxide (H(2)O(2)), superoxide anion (O(2)(-)) and nitric oxide (NO). An increase of NO and H(2)O(2) and a decrease of O(2)(-) were found. A direct relationship between peroxidase and nitric oxide synthase (iNOS) activities with enzyme expression was recorded, in contrast an inverse relationship between superoxide dismutase activity and expression was observed. If the high level of H(2)O(2) persists in time as well as a low level of peroxidase, oral pathologies are expected to occur. So, under this situation to study the modulation of enzymes involved in reactive oxygen species metabolism during oxidative stress in oral tissues could be very important in the managing of oral pathologies.