Thyroid hormones act as modulators of inflammation through their nuclear receptors (original) (raw)

Thyroid Hormones as Modulators of Immune Activities at the Cellular Level

Thyroid, 2011

Background: Increasing evidence suggests that thyroid hormones, L-thyroxine (T 4 ) and 3,3 0 ,5-triiodo-L-thyronine (T 3 ), are modulators of the immune response. In monocytes, macrophages, leukocytes, natural killer cells, and lymphocytes, a wide range of immune functions such as chemotaxis, phagocytosis, generation of reactive oxygen species (ROS), and cytokine synthesis and release are altered under hypo-and hyperthyroid conditions. Summary: Hyperthyroidism decreases the proinflammatory activities of monocytes and macrophages, whereas enhancement of phagocytosis and increased levels of ROS may occur during hypothyroidism. The expression of proinflammatory molecules such as macrophage inflammatory protein-1a and interleukin-1b increases in hypothyroidism. However, in Kupffer cells, proinflammatory activities such as the respiratory burst, nitric oxide synthase activity, and tumor necrosis factor-a expression may result from increased T 3 levels. Thyroid hormones also affect natural killer cell activity and cell-mediated immune responses. Still, for many immune cells no clear correlation has been found so far between abnormally high or low T 3 or T 4 levels and the effects observed on the immune responses. Conclusions: In this review we outline the contributions of thyroid hormones to different aspects of innate and adaptive immune responses. The relationship between thyroid hormones and immune cells is complex and T 3 and T 4 may modulate immune responses through both genomic and nongenomic mechanisms. Future studies of the molecular signaling mechanisms involved in this cross-talk between thyroid hormones and the immune system may support development of new strategies to improve clinical immune responses.

Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome

Frontiers in Cell and Developmental Biology, 2021

The interdependence between thyroid hormones (THs), namely, thyroxine and triiodothyronine, and immune system is nowadays well-recognized, although not yet fully explored. Synthesis, conversion to a bioactive form, and release of THs in the circulation are events tightly supervised by the hypothalamic–pituitary–thyroid (HPT) axis. Newly synthesized THs induce leukocyte proliferation, migration, release of cytokines, and antibody production, triggering an immune response against either sterile or microbial insults. However, chronic patho-physiological alterations of the immune system, such as infection and inflammation, affect HPT axis and, as a direct consequence, THs mechanism of action. Herein, we revise the bidirectional crosstalk between THs and immune cells, required for the proper immune system feedback response among diverse circumstances. Available circulating THs do traffic in two distinct ways depending on the metabolic condition. Mechanistically, internalized THs form a s...

Modulating the function of the immune system by thyroid hormones and thyrotropin

Immunology letters, 2017

Accumulating evidence suggests a close bidirectional communication and regulation between the neuroendocrine and immune systems. Thyroid hormones (THs) can exert responses in various immune cells, e.g., monocytes, macrophages, natural killer cells, and lymphocytes, affecting several inflammation-related processes (such as, chemotaxis, phagocytosis, reactive oxygen species generation, and cytokines production). The interactions between the endocrine and immune systems have been shown to contribute to pathophysiological conditions, including sepsis, inflammation, autoimmune diseases and viral infections. Under these conditions, TH therapy could contribute to restoring normal physiological functions. Here we discuss the effects of THs and thyroid stimulating hormone (TSH) on the immune system and the contribution to inflammation and pathogen clearance, as well as the consequences of thyroid pathologies over the function of the immune system.

Thyroid Hormone Action on Innate Immunity

Frontiers in Endocrinology, 2019

The interplay between thyroid hormone action and the immune system has been established in physiological and pathological settings. However, their connection is complex and still not completely understood. The thyroid hormones (THs), 3,3 ′ ,5,5 ′ tetraiodo-L-thyroxine (T4) and 3,3 ′ ,5-triiodo-L-thyronine (T3) play essential roles in both the innate and adaptive immune responses. Despite much research having been carried out on this topic, the available data are sometimes difficult to interpret or even contradictory. Innate immune cells act as the first line of defense, mainly involving granulocytes and natural killer cells. In turn, antigen presenting cells, macrophages and dendritic cells capture, process and present antigens (self and foreign) to naïve T lymphocytes in secondary lymphoid tissues for the development of adaptive immunity. Here, we review the cellular and molecular mechanisms involved in T4 and T3 effects on innate immune cells. An overview of the state-of-the-art of TH transport across the target cell membrane, TH metabolism inside these cells, and the genomic and non-genomic mechanisms involved in the action of THs in the different innate immune cell subsets is included. The present knowledge of TH effects as well as the thyroid status on innate immunity helps to understand the complex adaptive responses achieved with profound implications in immunopathology, which include inflammation, cancer and autoimmunity, at the crossroads of the immune and endocrine systems.

Interleukin-1 modulates endogenous thyroid hormone receptor gene transcription in liver cells

Journal of Endocrinology, 2007

One of the main characteristics of nonthyroidal illness (NTI) is a decrease in serum tri-iodothyronine, partly caused by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines have been associated with NTI in view of their capability to decrease D1 and thyroid hormone receptor (TR)b1 mRNA expression in hepatoma cells. Proinflammatory cytokine induction leads to activation of the inflammatory pathways nuclear factor (NF)kB and activator protein (AP)-1. The proinflammatory cytokine interleukin (IL)-1b decreases thyroid hormone receptor (TR)b1 mRNA in an NFkB-dependent way. The aim of this study was to unravel the effects of IL-1b on endogenous TRa gene expression in an animal model and in a liver cell line. The TRa gene product is alternatively spliced in TRa1 and TRa2, TRa2 is capable of inhibiting TRa1-induced gene transcription. We showed that both TRa1 and TRa2 mRNA decreased not only after lipopolysaccharide administration in liver of mice, but also after IL-1b stimulation of hepatoma cells (HepG2). Using the NFkB inhibitor sulfasalazine and the AP-1 inhibitor SP600125, it became clear that the IL-1b-induced decrease in TRa mRNA expression in HepG2 cells can only be abolished by simultaneous inhibition of NFkB and AP-1. The IL-1binduced TRa1 and TRa2 mRNA decrease in HepG2 cells is the result of decreased TRa gene promoter activity, as evident from actinomycin D experiments. Cycloheximide experiments showed that the decreased promoter activity is independent of de novo protein synthesis and therefore most likely due to posttranslational modifications such as phosphorylation or subcellular relocalization.

Inflammation in thyroid oncogenesis

American journal of cancer research, 2012

It is commonly accepted that cancer is linked to inflammation. The possible mechanisms by which inflammation can contribute to carcinogenesis include induction of genomic instability, alterations in epigenetic events and subsequent inappropriate gene expression, enhanced proliferation of initiated cells, resistance to apoptosis, aggressive tumor neovascularization, invasion through tumor-associated basement membrane and metastasis. Inflammation also affects immune surveillance and responses to therapy. In this review, we overview the current understanding of different aspects of thyroid cancer and inflammation. Several studies have strongly suggested an increased risk of PTC in patients with Hashimoto's thyroiditis (HT), the most common autoimmune disease in thyroid cancer. Furthermore, an intense immune infiltrate is often associated with papillary thyroid carcinoma (PTC), and might play a critical role in the regulation of carcinogenesis and in carcinoma progression. The chara...

Binding and functional effects of thyroid stimulating hormone on human immune cells

Journal of Clinical Immunology, 1990

The expression and functional relevance of thyroid stimulating hormone (TSH) receptors on human immune ceils were studied. Flow cytometric analysis was used to study the binding of biotinylated TSH to human peripheral blood mononuclear cells (PBMC) and various purified lymphoid populations. Our results indicate that the hormone binds well to monocytes and natural killer (NK) cells and marginally to purified tonsillar T and B lymphocytes. There was a significant increase in the binding of TSH to purified B cells that were activated in vitro with Staphylococcus aureaus Cowan. In contrast, the binding of TSH to T cells was unaltered when they were stimulated with phytohemagglutinin (PHA). While TSH increases DNA synthesis and intracellular cAMP levels of FRTL-5 rat thyroid cells, it did not have such stimulatory effects on lymphocytes. However, there was a moderate increase in Ig production by activated B lymphocytes when they were cultured in the presence of the hormone. A possible function for TSH as a link between the immune system and the thyroid is discussed.

Role of Cytokines in the Pathogenesis and Suppression of Thyroid Autoimmunity

Journal of Interferon & Cytokine Research, 2011

Autoimmune thyroid diseases (AITD) are one of the most common organ-specific autoimmune disorders, of which Hashimoto's thyroiditis (HT) and Graves' disease (GD) are 2 of the most common clinical expressions. HT is characterized by hypothyroidism that results from the destruction of the thyroid by thyroglobulin-specific T cell-mediated autoimmune response. In contrast, GD is characterized by hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. Cytokines play a crucial role in modulating immune responses that affect the balance between maintenance of selftolerance and initiation of autoimmunity. However, the role of cytokines is often confusing and is neither independent nor exclusive of other immune mediators. A regulatory cytokine may either favor induction of tolerance against thyroid autoimmune disease or favor activation and/or exacerbation of autoimmune responses. These apparently contradictory functions of a given cytokine are primarily influenced by the nature of co-signaling delivered by other cytokines. Consequently, a thorough understanding of the role of a particular cytokine in the context of a specific immune response is essential for the development of appropriate strategies to modulate cytokine responses to maintain or restore health. This review provides a summary of recent research pertaining to the role of cytokines in the pathogenesis of AITD with a particular emphasis on the therapeutic applications of cytokine modulation.