Nuclear Factor (NF)-κB-dependent Thyroid Hormone Receptor β1 Expression Controls Dendritic Cell Function via Akt Signaling

Abstract

Despite considerable progress in our understanding of the interplay between immune and endocrine systems, the role of thyroid hormones and their receptors in the control of adaptive immunity is still uncertain. Here, we investigated the role of thyroid hormone receptor (TR) ␤ 1 signaling in modulating dendritic cell (DC) physiology and the intracellular mechanisms underlying these immunoregulatory effects. Exposure of DCs to triiodothyronine (T 3 ) resulted in a rapid and sustained increase in Akt phosphorylation independently of phosphatidylinositol 3-kinase activation, which was essential for supporting T 3 -induced DC maturation and interleukin (IL)-12 production. This effect was dependent on intact TR␤ 1 signaling as small interfering RNA-mediated silencing of TR␤ 1 expression prevented T 3 -induced DC maturation and IL-12 secretion as well as Akt activation and IB-⑀ degradation. In turn, T 3 up-regulated TR␤ 1 expression through mechanisms involving NF-B, suggesting an autocrine regulatory loop to control hormone-dependent TR␤ 1 signaling. These findings were confirmed by chromatin immunoprecipitation analysis, which disclosed a new functional NF-B consensus site in the promoter region of the TRB1 gene. Thus, a T 3 -induced NF-B-dependent mechanism controls TR␤ 1 expression, which in turn signals DCs to promote maturation and function via an Akt-dependent but PI3K-independent pathway. These results underscore a novel unrecognized target that regulates DC maturation and function with critical implications in immunopathology at the crossroads of the immune-endocrine circuits.The endocrine and immune systems are interconnected via a bidirectional network in which hormones affect immune function, and, in turn, immune responses are reflected in neuroendocrine changes. This bidirectional communication is possible as both systems share common ligands (hormones and cytokines) and their specific receptors (1). Thyroid hormones (TH) 5 play critical roles in differentiation, growth, and metabolism. The classic genomic actions of TH are mediated by nuclear TH receptors (TR) that act mainly as hormone-inducible transcription factors. Several TR␣ and TR␤ isoforms are encoded by the TRA and TRB genes, respectively. The TR␣ 1 , TR␣ 2 , TR␤ 1 , and TR␤ 3 isoforms are widely expressed, whereas TR␤ 2 is predominantly restricted to the hypothalamus-pituitary axis (2). Recent emerging evidence has also characterized the interactions of TR with co-repressor proteins, namely the nuclear co-repressor and the silencing mediator of retinoid and TH receptors. These effects involve histone deacetylase activity that mediates TR silencing in the absence of triiodothyronine (T 3 ) and several co-activator proteins that exhibit histone acetylase activity in the presence of this hormone (2). However, the notion of classical or genomic mechanisms as unique actions mediated by TRs has been challenged in the past decade by descriptions of TH actions that involve extranuclear (nongenomic) effects in a variety of cell types. These TH-dependent ...

Thyroid hormone metabolism in innate immune cells

“…The effects of T 3 stimulation in dendritic cells are mediated via TRβ 1 and the Akt and NFκB pathways (Fig. 4) (Mascanfroni et al 2010). Besides the clear effects of altered extracellular TH levels, recent research has shown that several elements of intracellular TH metabolism 232:2 appear to be essential for adequate pro-inflammatory neutrophil and macrophage function.…”

“…The effects of T 3 stimulation are mediated via the TRβ1 receptor and the Akt and NFκB pathways independently of the PI3K pathway (Fig. 4) (Mascanfroni et al 2008(Mascanfroni et al , 2010. The promoter region of the TRβ1 gene contains an NFκB response element, which upregulates TRβ1 expression after T 3 stimulation, suggesting a regulatory feedback loop (Mascanfroni et al 2010).…”

“…T 3 binding to TRβ1 also activates cytoplasmic NFκB by initiating degradation of IκB so that NFκB can translocate to the nucleus and regulate gene transcription, including induction of TRβ1 transcription, which is an NFκB target gene, thus forming a regulatory feedback loop controlling TRβ1 levels (Mascanfroni et al 2008). Furthermore, binding of T 3 to cytoplasmic TRβ1 activates the Akt pathway, leading to a nuclear shift of phosphorylated Akt and increased chemokine (C-C motif) receptor type 7 (CCR7) expression, which prolongs cell viability and augments cell migration towards lymph nodes (Mascanfroni et al 2010. T 3 stimulation of DCs shifts the cells towards a more pro-inflammatory phenotype through induction of cell maturation, increased IL-12 production, improved antigen cross presentation and an enhanced ability to stimulate a cytotoxic T-cell response and trigger antigen-specific responses in vivo (Mascanfroni et al 2008, 2010, 2016.…”

“…4) (Mascanfroni et al 2008(Mascanfroni et al , 2010. The promoter region of the TRβ1 gene contains an NFκB response element, which upregulates TRβ1 expression after T 3 stimulation, suggesting a regulatory feedback loop (Mascanfroni et al 2010). Dexamethasone potently inhibits and even reverses the effects of T 3 in DCs (Montesinos et al 2012).…”

“…In dendritic cells, T 3 enters the cell via TH transporters MCT10 or LAT2 and binds to cytoplasmic TRβ1 (Gigena et al 2015 abstract 475, presented at the International Thyroid Congress). Upon binding of T 3 , TRβ1 translocates from the cytoplasm to the nucleus (Mascanfroni et al 2008(Mascanfroni et al , 2010. T 3 binding to TRβ1 also activates cytoplasmic NFκB by initiating degradation of IκB so that NFκB can translocate to the nucleus and regulate gene transcription, including induction of TRβ1 transcription, which is an NFκB target gene, thus forming a regulatory feedback loop controlling TRβ1 levels (Mascanfroni et al 2008).…”