Yu Jingcheng, Koenig Ronald J
Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical Center, Ann Arbor, 48109-0678, USA.
Endocrinology. 2006 Jul;147(7):3580-5. doi: 10.1210/en.2005-1443. Epub 2006 Apr 6.
Essentially all serious illness is associated with a decrease in circulating T(3), a condition known as the nonthyroidal illness syndrome. Substantial evidence suggests that a contributing factor to this syndrome is a cytokine-induced decrease in hepatic type 1 iodothyronine deiodinase (D1), an enzyme that converts T(4) to T(3). The type 1 deiodinase is induced at the transcriptional level by T(3), but illness-associated cytokines block this induction, resulting in decreased T(3) and hence a further decline in D1 expression. We demonstrated that IL-1 blocks the ability of T(3) to induce D1 in rat hepatocyte primary cultures and that forced expression of steroid receptor co- activator 1 (SRC-1) prevents this cytokine effect. This led us to test whether forced hepatic expression of SRC-1 can prevent the nonthyroidal illness syndrome in vivo. Pretreatment of endotoxin-treated mice with an adenovirus that expresses SRC-1, compared with a control adenovirus, prevented the endotoxin-induced decreases in hepatic D1 and plasma T(3). The data suggest that a cytokine-induced defect in T(3) receptor coactivators is an important component of this animal model of nonthyroidal illness and that the syndrome can be overcome by forced expression of the coactivator.
基本上，所有严重疾病都与循环中T3水平降低有关，这种情况被称为非甲状腺疾病综合征。大量证据表明，该综合征的一个促成因素是细胞因子诱导的肝脏1型碘甲状腺原氨酸脱碘酶（D1）减少，D1是一种将T4转化为T3的酶。1型脱碘酶在转录水平上由T3诱导，但疾病相关的细胞因子会阻断这种诱导，导致T3减少，进而导致D1表达进一步下降。我们证明，白细胞介素-1在大鼠肝细胞原代培养中阻断T3诱导D1的能力，而强制表达类固醇受体共激活因子1（SRC-1）可防止这种细胞因子效应。这促使我们测试在体内强制肝脏表达SRC-1是否可以预防非甲状腺疾病综合征。与对照腺病毒相比，用表达SRC-1的腺病毒对内毒素处理的小鼠进行预处理，可防止内毒素诱导的肝脏D1和血浆T3降低。数据表明，细胞因子诱导的T3受体共激活因子缺陷是这种非甲状腺疾病动物模型的一个重要组成部分，并且通过强制表达共激活因子可以克服该综合征。
