Nuclear Factor (NF)-kappa B-dependent Thyroid Hormone Receptor beta 1 Expression Controls Dendritic Cell Function via Akt Signaling

MASCANFRONI ID; MONTESINOS MM; ALAMINO VA; SUSPERREGUY S; NICOLA JP; ILARREGUI J; MASINI-REPISO AM; RABINOVICH GA; PELLIZAS CG

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Año: 2010 vol. 285 p. 9569 - 9582

0021-9258

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) beta1 signaling in modulating dendritic cell (DC) physiology and the intracellular mechanisms underlying these immunoregulatory effects. Exposure of DCs to triiodothyronine (T3) resulted in a rapid and sustained increase in Akt phosphorylation independently of phosphatidylinositol 3-kinase activation, which was essential for supporting T3-induced DC maturation and interleukin (IL)-12 production. This effect was dependent on intact TR beta1 signaling as small interfering RNA-mediated silencing of TR beta1 expression prevented T3-induced DC maturation and IL-12 secretion as well as Akt activation and I-kappaB-epsilon degradation. In turn, T3 up-regulated TR beta1 expression through mechanisms involving NF-kappaB, suggesting an autocrine regulatory loop to control hormone-dependent TR beta1 signaling. These findings were confirmed by chromatin immunoprecipitation analysis, which disclosed a new functional NF-kappaB consensus site in the promoter region of the TRB1 gene. Thus, a T3-induced NF-kappaB-dependent mechanism controls TR beta1 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.