Impact of Thyroid Hormones in the initiation of the immune response

PELLIZAS CG

Gramado, Brasil

Simposio; XIII Latin American Thyroid Congress; 2009

Latin American Thyroid Society

In spite of 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)â1 signaling in modulating dendritic cell (DC) physiology and the intracellular mechanisms underlying these immunoregulatory effects. Exposure of DCs to triiodothyronine (T3) resulted in rapid and sustained increase in Akt phosphorylation independently of PI3K activation, which was essential for supporting T3-induced DC maturation and interleukin (IL)-12 production. This effect was dependent on intact TRâ1 signaling as siRNA-mediated silencing of TRâ1 expression prevented T3-induced DC maturation and IL-12 secretion as well as Akt activation and IêB-å degradation. In turn, T3 up-regulated TRâ1 expression through mechanisms involving NF-êB, suggesting an autocrine regulatory loop to control hormone-dependent TRâ1 signaling. These findings were confirmed by chromatin immunoprecipitation analysis which disclosed a new functional NF-êB consensus site in the promoter region of the TRB1 gene. Thus, a T3-induced NF-êB-dependent mechanism controls TRâ1 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 cross-roads of immune-endocrine circuits.