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This Thematic Issue presents reviews of recent studies on effects of thyroid hormones and certain metabolites that are linked to human diseases, providing a general update of the topic. I have been the guest editor for thematic issues of IEMAMC for three times, in 2006, 2011 and 2015, and over these 10 years my knowledge of the nongenomic effects of thyroid hormone has improved considerably. First issue was dedicated to the nongenomic effects of various hormones endowed with classical nuclear receptors, and included a chronology of the earliest reported nongenomic effects of thyroid hormones. Second issue was centered on thyroid hormone nongenomic mechanisms in skeletal muscle and nerve cells, mainly, but not exclusively, dealing with effects mediated by integrin alphaVbeta3. In the current issue, the coverage of thyroid hormone actions is wider, including also nuclear classical effects, the cognitive processes and effects of some hormone metabolites that are particularly interesting from pharmacological point of view. Why? When a new surprising discovery is published, such as the seminal paper by Bergh et al., in 2005, showing that the integrin alphaVbeta3 was the long-searched plasma membrane receptor for thyroid hormones, it can of course dominate the scenery for years, and other researchers in this field will use this new piece of information in their studies to understand the physio-pathological effects of thyroid hormones. The Bergh et al. paper showed that binding by thyroxine to the integrin alphaVbeta3 gives rise to a downstream signaling that causes MAPK activation and tumor cell proliferation. This has so to say been the ‘Big Bang’ of nongenomic effects of thyroid hormones. After ten years of the integrin story, we can now observe how many things have changed in our knowledge about the role of thyroid hormones in animal physiology. However, actually the integrin story began before alphaVbeta3 was recognized as a plasma membrane thyroid hormone receptor. The group of Davis and Davis showed, in 2004, that various effects of thyroid hormone on the actions of epidermal growth factor and transforming growth factor-alpha were mediated by cAMP-dependent protein kinase II. The crosstalk between thyroid hormones and growth factors reported in that paper would eventually lead to the integrin; alphaVbeta3 was ‘in nuce’ although it was not clear at that time. Now, this interaction of thyroid hormones with growth factors is coming of age and may lead us far, to different and still unknown aspects of physiology and pathology, as it can be observed from some of the contributions in this issue.

Genomic actions of thyroid hormone require the intranuclear binding by nuclear thyroid hormone receptors (TRs) of 3,5,3’-triiodo-L-thyronine (T3). Nongenomic actions of the hormone have been described that are initiated at the plasma membrane, in cytoplasm or in the mitochondrion. These are complex processes associated with maintenance of the cytoskeleton, control of cell respiration, cell proliferation—including tumor cell proliferation and angiogenesis—and nervous system function. We briefly review here the nature of the proteins which are now appreciated to initiate nongenomic actions of the hormone when they bind T3 or L-thyroxine (T4). These receptor proteins for nongenomic effects include truncated isoforms of TRalpha, cytoplasmic intact TRbeta, certain cytoplasmic enzymes and a structural protein of the plasma membrane, integrin alphaVbeta3.

Nongenomic effects of thyroid hormones typically start at the cell surface and do not primarily involve the classical nuclear receptors, but rather a plasma membrane receptor site identified about ten years ago on the integrin v3. Transduction of the thyroid hormone signal from this integrin receptor involves activation of the MAPK pathway and may lead to events such as angiogenesis or tumor cell proliferation. This review focuses on the interaction of thyroid hormones with growth factors, in fact the integrin v3 has been reported to a be a co-receptor for several growth factors such as EGF, IGF-1 and the FGF family, but also for small molecules like resveratrol. Binding of the ligand to integrin v3 is inhibited by tetrac, a metabolite of L-thyroxine, and by its nanoparticulate formulation nanotetrac. Recent microarray studies on tumor cells have shown that tetrac has antiinflammatory effects that are mediated by integrin v3, and tetrac can downregulate the expression of several interleukin genes. Crosstalk between thyroid hormones and vascular growth factors is important for cell migration, vascular calcification and the angiogenic process. Thyroid hormones also show pleiotropic effects on osteoblast function and differentiation, as well as in early pregnancy. The importance of thyroid hormone interaction with neurotrophins and interleukins has also been examined. With integrin v3 firmly established as the plasma membrane receptor future studies will focus on the crosstalk between thyroid hormones and growth factors in order to verify the efficiency of new pharmacological tools, such as nanotetrac.

P-glycoprotein (P-gp; multidrug resistance pump 1, MDR1; ABCB1) is a plasma membrane efflux pump that when activated in cancer cells exports chemotherapeutic agents. Transcription of the P-gp gene (MDR1) and activity of the P-gp protein are known to be affected by thyroid hormone. A cell surface receptor for thyroid hormone on integrin αvβ3 also binds tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T4) that blocks nongenomic actions of T4 and of 3,5,3′-triiodo-L-thyronine (T3) at αvβ3. Covalently bound to a nanoparticle, tetrac as nanotetrac acts at the integrin to increase intracellular residence time of chemotherapeutic agents such as doxorubicin and etoposide that are substrates of P-gp. This action chemosensitizes cancer cells. In this review, we examine possible molecular mechanisms for the inhibitory effect of nanotetrac on P-gp activity. Mechanisms for consideration include cancer cell acidification via action of tetrac/nanotetrac on the Na+/H+ exchanger (NHE1) and hormone analogue effects on calmodulin-dependent processes and on interactions of P-gp with epidermal growth factor (EGF) and osteopontin (OPN), apparently via αvβ3. Intracellular acidification and decreased H+ efflux induced by tetrac/nanotetrac via NHE1 is the most attractive explanation for the actions on P-gp and consequent increase in cancer cell retention of chemotherapeutic agent-ligands of MDR1 protein.

Thyroid hormones, T3(triiodothyronine) and T4(thyroxine), induce a variety of long-term effects on important physiological functions, ranging from development and growth to metabolism regulation, by interacting with specific nuclear or cytosolic receptors. Extranuclear or nongenomic effects of thyroid hormones are mediated by plasma membrane or cytoplasmic receptors, mainly by αvβ3 integrin, and are independent of protein synthesis. A wide variety of nongenomic effects have now been recognized to be elicited through the binding of thyroid hormones to this receptor, which is mainly involved in angiogenesis, as well as in cell cancer proliferation. Several signal transduction pathways are modulated by thyroid hormone binding to αvβ3 integrin: protein kinase C, protein kinase A, Src, or mitogen-activated kinases. Thyroid hormone-activated nongenomic effects are also involved in the regulation of Na+-dependent transport systems, such as glucose uptake, Na+/K+-ATPase, Na+/H+exchanger, and amino acid transport System A. Of note, the modulation of these transport systems is cell-type and developmental stage-dependent. In particular, dysregulation of Na+/K+-ATPase activity is involved in several pathological situations, from viral infection to cancer. Therefore, this transport system represents a promising pharmacological tool in these pathologies.

Interaction between thyroid hormones and the immune system is reported in the literature. Thyroid hormones, thyroxine, T-4, but also T-3, act non-genomically through mechanisms that involve a plasma membrane receptor alpha v beta 3 integrin, a co-receptor for insulin-like growth factor-1 (IGF-1). Previous data from our laboratory show a crosstalk between thyroid hormones and IGF-1 because thyroid hormones inhibit the IGF-1-stimulated glucose uptake and cell proliferation in L-6 myoblasts, and the effects are mediated by integrin alpha v beta 3. IGF-1 also behaves as a chemokine, being an important factor for tissue regeneration after damage. In the present study, using THP-1 human leukemic monocytes, expressing alpha v beta 3 integrin in their cell membrane, we focused on the crosstalk between thyroid hormones and either IGF-1 or monocyte chemoattractant protein-1 (MCP-1), studying cell migration and proliferation stimulated by the two chemokines, and the role of alpha v beta 3 integrin, using inhibitors of alpha v beta 3 integrin and downstream pathways. Our results show that IGF-1 is a potent chemoattractant in THP-1 monocytes, stimulating cell migration, and thyroid hormone inhibits the effect through alpha v beta 3 integrin. Thyroid hormone also inhibits IGF-1-stimulated cell proliferation through alpha v beta 3 integrin, an example of a crosstalk between genomic and non-genomic effects. We also studied the effects of thyroid hormone on cell migration and proliferation induced by MCP-1, together with the pathways involved, by a pharmacological approach and docking simulation. Our findings show a different downstream signaling for IGF-1 and MCP-1 in THP-1 monocytes mediated by the plasma membrane receptor of thyroid hormones, integrin alpha v beta 3.

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 stable complex with their specific receptors, which, upon direct or indirect binding to DNA, triggers a genomic response by activating transcriptional factors, such as those belonging to the Wnt/β-catenin pathway. Alternatively, THs engage integrin αvβ3 receptor on cell membrane and trigger a non-genomic response, which can also signal to the nucleus. In addition, we highlight THs-dependent inflammasome complex modulation and describe new crucial pathways involved in microRNA regulation by THs, in physiological and patho-physiological conditions, which modify the HPT axis and THs performances. Finally, we focus on the non-thyroidal illness syndrome in which the HPT axis is altered and, in turn, affects circulating levels of active THs as reported in viral infections, particularly in immunocompromised patients infected with human immunodeficiency virus.