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

BARREIRO ARCOS M.L. ; STERLE H.A.; PAULAZO M.A.; VALLI E.; KLECHA A.J.; ISSE B; PELLIZAS C; FARÍAS R.; CREMASCHI G.A.

JOURNAL OF CELLULAR PHYSIOLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: Philadelphia; Año: 2011 vol. 226 p. 3208 - 3218

0021-9541

ABSTRACT: Thyroid hormones (THs) exert a broad range of actions on development, growth and cell differentiation by both genomic and non genomic mechanisms. THs regulate lymphocyte function, but the participation of nongenomic actions is still unknown. Here the contribution of both genomic and non genomic effects on TH-induced division of T cells was studied by using free and non-cell 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) z isoform to cell membranes, extracellular-signal-regulated kinases (ERK1/2) phosphorylation and nuclear factor-kB (NF-kB) activation. The signaling cascade include sphingomielinases acting upstream the activation of PKCz isoform, while ERK and NF-kB are activated downstream this PKC isoenzyme. Both free and THs-ag increased the protein and mRNA levels of TH nuclear receptor TRa1, 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 PKCz inhibition. These results indicate that THs, by triggering a nongenomic signaling cascade that involves Smases-mediated activation of PKCz, lead to ERK 1/2 and NF-kB 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.