Nuclear hormone receptor ligands are known to modulate innate immunity by dampening the immune response induced by pathogens. Here, we report that unlike other ligands, 3,3′,5-triiodo-l-thyronine (T3) induced the type 1 IFN response and expression of IFN-stimulated genes (ISGs). T3 action was found to be significantly amplified at supraphysiological concentrations (SPC) and in combination with double-stranded RNA mimic polyinosinic–polycytidylic acid. Induction by T3 was due to non-genomic mechanisms involving integrin binding, calcium mobilization, and phosphatidyl-inositol 3-kinase–AKT pathways, but was independent of TLR3, RIG-I, and IFN-β1 pathways. Whereas siRNA-induced knockdown of RNA-activated protein kinase (PKR) was found to abrogate the T3-induced expression of select ISGs, expression of other T3-induced ISGs was strongly induced by PKR knockdown, indicating the differential role of PKR in modulating T3 action. Together, we describe a novel role of T3 in modulating the innate immune response and identify the importance of PKR in regulating T3-induced immune activation. These findings have important implications in the basic understanding of the mechanisms of T3 function at SPCs and crosstalk involved in the thyroid hormone function and the innate immune response.

已知核激素受体配体通过抑制病原体诱导的免疫反应来调节先天免疫。在此，我们报道与其他配体不同，3,3',5-三碘-l-甲状腺氨酸 (T3) 诱导 1 型 IFN 反应和 IFN 刺激基因 (ISG) 的表达。发现 T3 作用在超生理浓度 (SPC) 下并与双链 RNA 模拟聚肌苷-聚胞苷酸结合时显着增强。 T3 的诱导是由于涉及整合素结合、钙动员和磷脂酰肌醇 3-激酶 -AKT 途径的非基因组机制，但独立于 TLR3、RIG-I 和 IFN-β1 途径。虽然 siRNA 诱导的 RNA 激活蛋白激酶 (PKR) 敲低被发现可以消除 T3 诱导的选定 ISG 的表达，但其他 T3 诱导的 ISG 的表达却受到 PKR 敲低的强烈诱导，表明 PKR 在调节 T3 中的不同作用行动。我们共同描述了 T3 在调节先天免疫反应中的新作用，并确定了 PKR 在调节 T3 诱导的免疫激活中的重要性。这些发现对于基本了解 SPC 的 T3 功能机制以及涉及甲状腺激素功能和先天免疫反应的串扰具有重要意义。