Triiodothyronine-stimulated dendritic cell vaccination boosts antitumor immunity against murine colon cancer.

Given the ability of dendritic cells (DCs) to modulate other immune players, their manipulation holds great potential for inducing efficient antitumor immunity. However, DC vaccine manufacturing deserve optimization since tumor cell cargo and DC functional state induced by maturation signals influence their in vivo immunogenic potential. We reported that triiodothyronine (T3) stimulates mice DCs' maturation and their ability to promote pro-inflammatory and cytotoxic T-cell responses. This study aimed to evaluate the efficacy of T3-conditioned DC vaccination in a murine model of colon carcinoma, deciphering the molecular players involved; and to examine the effects of T3 on the maturation and activation of human DCs (huDCs). Bone marrow-derived DCs were exposed to T3 and MC38 cancer cells that underwent cell death (MC38-Apo/Nec) by UVB irradiation. Our results showed that MC38-Apo/Nec cells are efficiently uptaken by DCs and that T3 upregulates CD86 expression with increased production of the pro-inflammatory cytokines IL-12, IL-6 and TGF-ß. In a colon cancer model, vaccination with T3-stimulated and tumor antigen-loaded DCs inhibited tumor growth in wild type mice, an effect that was eliminated in IL-17-deficient animals. Notably, secretion of high levels of IFN-γ and IL-17, induction of Th1, Th17 and tumor-specific cytotoxic T lymphocytes characterized the antitumor response upon vaccination. Moreover, our initial findings demonstrated a significant increase in CD86 expression and IL-12 production by huDCs induced by T3. Overall, these results reinforce the adjuvant properties of T3-conditioned DCs to potentiate T-cell-mediated antitumor immunity and support promising advances in the translation process to human oncotherapy.

Nuclear factor (NF)-kappaB-dependent thyroid hormone receptor beta1 expression controls dendritic cell function via Akt signaling.

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) beta(1) signaling in modulating dendritic cell (DC) physiology and the intracellular mechanisms underlying these immunoregulatory effects. Exposure of DCs to triiodothyronine (T(3)) resulted in a rapid and sustained increase in Akt phosphorylation independently of phosphatidylinositol 3-kinase activation, which was essential for supporting T(3)-induced DC maturation and interleukin (IL)-12 production. This effect was dependent on intact TR beta(1) signaling as small interfering RNA-mediated silencing of TR beta(1) expression prevented T(3)-induced DC maturation and IL-12 secretion as well as Akt activation and I kappaB-epsilon degradation. In turn, T(3) up-regulated TR beta(1) expression through mechanisms involving NF-kappaB, suggesting an autocrine regulatory loop to control hormone-dependent TR beta(1) 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 T(3)-induced NF-kappaB-dependent mechanism controls TR beta(1) 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 the immune-endocrine circuits.

Differential modulation of liver and pituitary triiodothyronine and 9-cis retinoid acid receptors by insulin-like growth factor I in rats.

Triiodothyronine (T(3)) exerts most of its effects through nuclear thyroid hormone receptors (TRs) that bind mainly as heterodimers with retinoid-X receptors (RXRs) to thyroid hormone response elements in target genes. It is well known that T(3) activates the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis in rats. In turn, IGF-I inhibits the T(3)-induced GH production in cell cultures. The impact of IGF-I on T(3) action has only been partially explored. We have presented evidence that IGF-I feeds back to limit specific metabolic actions of T(3) in rat liver through a downregulation of nuclear TR number and its mRNA expression. We have also found that IGF-I injected to rats inhibited pituitary GH production. In this study we aimed at exploring whether the IGF-I-induced feedback loop on T(3)-action in the liver also operates in the pituitary gland. The mechanism of the liver TR mRNA reduction induced by IGF-I was also studied. We evaluated the effect of recombinant human (rh) IGF-I administration (240 microg/100 g of body weight subcutaneously every 12 hours for 48 hours) to adult male Wistar rats on TR and RXR proteins (Western blot) from pituitary, liver, brain, and thyroid and TR mRNA (Northern blot) from pituitary and liver. The transcriptional rate of liver TR gene (run-on assay) was also determined. In pituitary, TR protein and TR mRNA isoforms were reduced by rhIGF-I. No changes in TR proteins in brain and thyroid were observed. Nuclear run-on assay revealed that IGF-I reduced the TR gene transcriptional rate in liver. A significant increase in RXR proteins in liver and pituitary without changes in thyroid and brain was induced by IGF-I. In conclusion, these results indicate that in pituitary, IGF-I downregulates TR expression, similarly as previously found in liver. A reduced transcriptional rate of TR gene is implicated in the IGF-I effect on the liver. The increase in RXR protein levels may be also involved in the expression of T(3) specific actions in liver and pituitary.