Suppression of iodide uptake and thyroid hormone synthesis with stimulation of the type I interferon system by double-stranded ribonucleic acid in cultured human thyroid follicles.
Suppression of iodide uptake and thyroid hormone synthesis with stimulation of the type I interferon system by double-stranded ribonucleic acid in cultured human thyroid follicles.
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DOI：
10.1210/en.2006-1638
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发表时间：
2007-07
期刊：
影响因子：
4.8
通讯作者：
K. Yamazaki;Koichi Suzuki;E. Yamada;Tetsu Yamada;F. Takeshita;M. Matsumoto;T. Mitsuhashi;T. Obara;K. Takano;Kanji Sato
中科院分区：
文献类型：
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作者：
K. Yamazaki;Koichi Suzuki;E. Yamada;Tetsu Yamada;F. Takeshita;M. Matsumoto;T. Mitsuhashi;T. Obara;K. Takano;Kanji Sato
虽然病毒感染被认为与亚急性甲状腺炎和自身免疫性甲状腺疾病有关，但在感染前驱期或亚临床感染期间甲状腺功能可能发生的变化在很大程度上仍然未知。最近，研究表明病原体相关的分子模式通过产生I型干扰素（IFN）刺激toll样受体（TLR）并激活先天免疫反应。我们利用人甲状腺滤泡培养系统，将新合成的甲状腺激素释放到生理浓度的人TSH培养基中，研究了病毒双链RNA （dsRNA）的化学类似物聚肌苷-多胞酸[Poly(I:C)]对TSH诱导的甲状腺功能的影响。甲状腺细胞表达与TSH受体相似的dsRNA配体（tlr3、CD14和视黄酸诱导蛋白-1）。DNA微阵列和实时PCR分析显示，dsRNA增加了TLR3、ifn - β、ifn调节因子、促炎细胞因子和I类主要组织相容性复合体（MHC） mRNA的表达，而与甲状腺激素生成相关的基因（钠/碘化物同调体、过氧化物酶、脱碘酶）被抑制。根据这些数据，Poly（I:C）对tsh诱导的125I摄取和激素合成具有剂量依赖性，同时125I- t3 /125I- t4释放到培养基中的比例降低，而肽聚糖、脂多糖或未甲基化的CpG DNA、TLR2、TLR4和TLR9的配体分别对其无显著影响。Poly（I:C）的这些抑制作用不会被针对TLR3的中和抗体和抗ifn α / β受体抗体阻断。这些体外研究结果提示，当甲状腺细胞被某些病毒感染时，在甲状腺细胞内形成的dsRNA可能是甲状腺功能障碍的一个原因，导致自身免疫性甲状腺炎的发展。
Although viral infection is thought to be associated with subacute thyroiditis and probably with autoimmune thyroid disease, possible changes in thyroid function during the prodromal period of infection or subclinical infection remain largely unknown. Recently, it was shown that pathogen-associated molecular patterns stimulate Toll-like receptors (TLR) and activate innate immune responses by producing type I interferons (IFN). Using a human thyroid follicle culture system, in which de novo synthesized thyroid hormones are released into the culture medium under physiological concentrations of human TSH, we studied the effects of polyinosinic-polycytidylic acid [Poly(I:C)], a chemical analog of viral double-stranded RNA (dsRNA), on TSH-induced thyroid function. Thyrocytes expressed ligands for dsRNA (TLR 3, CD14, and retinoic-acid-inducible protein-1) comparable with the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3, IFN-beta, IFN-regulating factors, proinflammatory cytokines, and class I major histocompatibility complex (MHC), whereas genes associated with thyroid hormonogenesis (sodium/iodide symporter, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I:C) suppressed TSH-induced 125I uptake and hormone synthesis dose dependently, accompanied by a decrease in the ratio of 125I-T3/125I-T4 released into the culture medium, whereas peptidoglycan, lipopolysaccharides, or unmethylated CpG DNA, ligands for TLR2, TLR4, and TLR9, respectively, had no significant effect. These inhibitory effects of Poly(I:C) were not blocked by a neutralizing antibody against TLR3 and an anti-IFN alpha/beta receptor antibody. These in vitro findings suggest that when thyrocytes are infected with certain viruses, dsRNA formed intracellularly in thyrocytes may be a cause for thyroid dysfunction, leading to development of autoimmune thyroiditis.