The Thyroid Hormone Receptors as Modulators of Skin Proliferation and Inflammation

Abstract

The actions of thyroid hormones are mediated by binding to nuclear receptors, TR␣ 4 and TR␤, that act as ligand-dependent transcription factors by association, generally as heterodimers with retinoid X receptors, with thyroid hormone response elements located in regulatory regions of target genes (1). TRs can also modulate expression of genes that do not contain a hormone response element by modulating the activity of other transcription factors and signaling pathways (2), including activator protein-1 (AP-1)-, cyclic AMP-response element-, and nuclear factor-B (NF-B)-dependent pathways (3-7).Studies with knock-out (KO) mice for TRs obtained by homologous recombination have indicated that KO mice for ␣1 and ␤ TR isoforms have different phenotypes (8 -10) and that the double KO mice, surprisingly, survive (11), indicating that these receptors are not required for viability. Although these animals show extreme resistance to thyroid hormones, they exhibit a milder phenotype than hypothyroid mice, indicating divergent consequences for hormone versus receptor deficiency for some actions.Although the skin is a target tissue for thyroid hormone action, no studies on the skin phenotype in TR KO mice have been reported. TR␣ and TR␤ mRNAs are present in the skin (12-15), and these receptors can regulate either positively or negatively the expression of selected keratins in cultured cells (16 -19). Clinical evidence (19 -27) as well as studies in hypothyroid mice and rats (28 -30) also suggest that thyroid hormones could be involved in epidermal proliferation and differentiation, hair growth, and wound healing besides affecting the function of dermal fibroblasts. A question emerging from these studies is how to distinguish between effects due to altered thyroid hormone levels and effects due to expression of specific TR isoforms.The TR KO mice represent an excellent model for the analysis of the role of these receptors in the skin and its response to hyperproliferative stimuli. Topical application of 12-O-tetradecanolyphorbol-13-acetate (TPA) to mouse skin is a well known model for induction of skin hyperproliferation and also promotes a strong inflammatory reaction that activates multiple immunostimulatory pathways. The skin response to TPA is associated with activation of several intracellular pathways (e.g. mitogen-activated protein kinases (MAPKs), AKT, NF-B, STAT3, and AP-1) as well as an increase in the content of chemical mediators, such as cytokines, chemokines, vasoactive peptides, prostaglandins, leukotrienes, and nitric oxide among others (31)(32)(33)(34).In this work, we have investigated skin proliferation and inflammation, before and after TPA application, in mice lacking TR␣1, TR␤, or both genes, comparing these responses with those of hypothyroid animals to distinguish the specific contributions of receptor expression and activation. We found that TRs and thyroid hormones are required for skin homeostasis after TPA treatment and that both receptor genes contribute to

Thyroid Disease and Oral Lichen Planus as Comorbidity: A Prospective Case-Control Study

“…Clinical evidence and studies in hypothyroid rats proposed that thyroid hormone might be involved in hair growth and epidermal proliferation and differentiation [36]. Consistent with other epidemiological studies, the research at hand suggests that hypothyroidism is the most common thyroid comorbidity seen in lichen planopilaris [37] and OLP patients [16].…”

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

“…However, we cannot exclude the possibility of multiple suppressive effects of TR on fibrogenesis. For instance, inflammation appears to play an important role on the initial stages of fibrosis, sensitizing cells for TGF-β/SMAD activation (4, 7), and we have previously shown that TR deletion increases inflammatory responses in the skin (50). Although the role of TRs in the inflammatory reaction to CCl4 or bleomycin administration remains to be explored, it is possible that a reduced inflammation as a consequence of increased TR signaling could also play a role in the observed antifibrotic effects of the thyroid hormones in vivo.…”

“…administration of CCl4 and to a bleomycin model of skin fibrosis, as detailed in the SI Appendix. Double KO mice for TRα1 and TRβ have been described (50). Experimental procedures for transfections, luciferase reporter assays, Western blot, GST pull-down assays, coimmunoprecipitation, mRNA determination by real-time PCR, and chromatin immunoprecipitation assays have been published previously and are described together with the antibodies and primers used in SI Appendix.…”

Maternal-Fetal Thyroid Interactions

“…TRs can also regulate the activity of genes that do not contain a TRE through "cross-talk" with other transcription factors (TF) that stimulate target gene expression [28,86]. Both receptors and coregulators are targets for phosphorylation (P) by signal transduction pathways stimulated by hormones and growth factors [84,85]. Thus, the nuclear actions of T3 are sensitive to inhibitors of transcription and translation and have a latency of hours to days [9,73].…”

“…Activity is regulated by an exchange of corepressor (CoR) and coactivator (CoA) complexes. Negative TREs (nTRE) can mediate ligand-dependent transcriptional repression, although in this case the role of coactivators and corepressors is not well defined [73,85]. TRs can also regulate the activity of genes that do not contain a TRE through "cross-talk" with other transcription factors (TF) that stimulate target gene expression [28,86].…”