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

Abstract

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 sphingomyelinases 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.

Integrin αvβ3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells

“…Pathway analysis and our previous findings in murine TCL models 14 suggest that NF-kB mediates downstream of the THactivated avb3 integrin signaling. We now confirm that in human TCLs, TH also induced the activation and therefore nuclear translocation of NF-kB ( Figure 3E).…”

“…We demonstrated that THs induce murine TCL proliferation in vitro 13,14 by activating both nuclear and membrane receptors. To determine whether THs also contribute to maintaining proliferation in human malignant T cells, we first characterized the expression of nuclear TRa and TRb, and the putative membrane integrin avb3 receptors, in a panel of TCL cell lines.…”

“…[10][11][12] We recently demonstrated that physiological levels of THs can stimulate the proliferation of murine TCLs through complementary intracellular pathways involving nuclear and membrane receptors, ultimately leading to protein kinase C, extracellular signal-regulated kinase 1/2 (ERK1/2), and nuclear factor kB (NF-kB) activation. 13,14 In this context, a hypothyroid state would be beneficial for TCL patients; however, this strategy is associated with potentially harmful effects that preclude its clinical application. We hypothesized that targeting integrin avb3 could help to overcome this limitation; however, the mechanistic contributions of integrin avb3 to human TCL survival are unknown.…”

Thyroid signaling in immune organs and cells of the teleost fish rainbow trout (Oncorhynchus mykiss)

“…: Refs. [5,26,42]), and they mediate a number of immune effects exerted by THs [6,49]. Here we sought to unravel whether THRs are also expressed in immune organs and cells of teleosts and to evidence the effects of TH status on immune function.…”

Maternal Hyperthyroidism and Developing Hematopoiesis Dysfunction

“…In human early hematopoietic cells, THs might play a significant action in the regulation of the growth (Gruber et al, 1999;Grymuła et al, 2007;Kawa et al, 2010). More importantly, the genomic and nongenomic actions of THs might be regulated these mechanisms (Gruber et al, 1999;Milne et al, 1999;Dorshkind and Horseman, 2000;Porter and Mandel, 2000;Bauer et al, 2001;Omazic et al, 2001;Marongiu et al, 2004;Kawa et al, 2010;Barreiro Arcos et al, 2011;Franchini et al, 2011;Kandir and Keskin, 2016). In addition, Kawa et al (2010) reported that any change in the gene expressions of thyroid receptors (TRs; α and β) might change the hematopoietic progenitors.…”