NUCLEAR FACTOR KAPPA B-DEPENDENT THYROID HORMONE RECEPTOR B1- EXPRESSION CONTROLS DENDRITIC CELL FUNCTION VIA AKT SIGNALING

IVAN D. MASCANFRONI; MARIA D. MONTESINOS; VANINA ALAMINO; SEBASTIAN SUSPERREGUY; JUAN NICOLA; JUAN M. ILARREGUI; ANA M. MASINI-REPISO; GABRIEL A. RABINOVICH; CLAUDIA G. PELLIZAS

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: BALTIMORE, MD ; Año: 2010 vol. 285 p. 9569 - 9582

0021-9258

Despite considerable progress in our understanding of theinterplay between immune and endocrine systems, the role ofthyroid hormones and their receptors in the control of adaptiveimmunity is still uncertain. Here, we investigated the role ofthyroid hormone receptor (TR)b1 signaling in modulating dendriticcell (DC) physiology and the intracellular mechanismsunderlying these immunoregulatory effects. Exposure of DCs totriiodothyronine (T3) resulted in a rapid and sustained increasein Akt phosphorylation independently of phosphatidylinositol3-kinase activation, which was essential for supporting T3-inducedDC maturation and interleukin (IL)-12 production. Thiseffect was dependent on intact TRb1 signaling as small interferingRNA-mediated silencing of TRb1 expression preventedT3-induced DC maturation and IL-12 secretion as well as Aktactivation and IkB-a degradation. In turn, T3 up-regulatedTR1 expression through mechanisms involving NF-
B, suggestingan autocrine regulatory loop to control hormone-dependentTRb1 signaling. These findings were confirmed bychromatin immunoprecipitation analysis, which disclosed anew functional NF-kB consensus site in the promoter region ofthe TRB1 gene. Thus, a T3-induced NF-kB-dependent mechanismcontrols TRb1 expression, which in turn signals DCs topromote maturation and function via an Akt-dependent butPI3K-independent pathway. These results underscore a novelunrecognized target that regulates DC maturation and functionwith critical implications in immunopathology at the crossroadsof the immune-endocrine circuits.