A study on the interferon-γ activated intracellular signal transduction pathway in the thyroid

【IRF-1研究】干扰素调节因子-1 （Interferon regulatory factor-1, IRF-1）是干扰素（IFN）诱导的转录因子，在甲状腺中表达，参与甲状腺功能的调节和自身免疫性甲状腺疾病（autoimmune thyroid disease， AITD）的发病机制。为了研究IRF-1在AITD发展中的作用，我们在缺乏IRF-1基因的桥本甲状腺炎动物模型非肥胖糖尿病（NOD）小鼠中评估了甲状腺炎的频率和严重程度。虽然超过80%的14周龄碘摄入IRF-1 +/+和+/-小鼠发生淋巴细胞性甲状腺炎（LT），但没有-/-小鼠发生LT。相反，24周龄小鼠和免疫甲状腺球蛋白（Tg）的小鼠发生甲状腺炎，无论IRF-1是否存在。在后者中，甲状腺炎的严重程度无显著差异。在IRF-1 -/-小鼠中，脾脏中CD8+T细胞和IFN-γ分泌减少。这些结果表明，CD8+ T细胞和Th1反应参与了IRF-1缺陷NOD小鼠碘诱导的LT的发展。然而，NOD小鼠自发性甲状腺炎和tg诱导的甲状腺炎可能涉及不同的机制。【PKR研究】双链RNA （dsRNA）依赖性蛋白激酶（PKR）在抗病毒应答和细胞功能调控中发挥重要作用。我们证实PKR存在于FRTL-5大鼠甲状腺细胞中。在FRTL-5细胞中添加dsRNA可导致真核起始因子-2和iκBα磷酸化，并诱导NFκB结合。此外，在dsrna刺激的细胞中，I型IFN，特别是IFN-β， IRF-1基因表达和STAT-1磷酸化被诱导。这些结果提示dsRNA激活的信号转导通路可能参与甲状腺功能的调节，并可能参与AITD的发病机制。

【IRF-1 study】Interferon regulatory factor-1 (IRF-1), an interferon (IFN)-inducible transcription factor, is expressed in the thyroid and implicated in the regulation of thyroid function and in the pathogenesis of autoimmune thyroid disease (AITD). To examine the role of IRF-1 in the development of AITD, the frequency and severity of thyroiditis were assessed in nonobese diabetic (NOD) mice, an animal model of Hashimoto's thyroiditis, lacking IRF-1 gene. While more than 80 % of 14 week-old iodide ingested IRF-1 +/+ and +/- mice developed lymphocytic thyroiditis (LT), no -/- mice developed LT. In contrast, 24 week-old mice and thyroglobulin (Tg)immunized mice developed thyroiditis regardless of IRF-1. In the latter, no significant difference was found in the severity of thyroiditis. In IRF-1 -/- mice, CD8+T cells and IFN-γ secretion were decreased in the spleen. These results suggest that CD8+ T cells and Th1 reaction are involved in the development of iodide-induced LT in IRF-1 deficient NOD mice. However, different mechanism may be involved in spontaneous and Tg-induced thyroiditis in NOD mice.【PKR study】Double-stranded RNA (dsRNA) dependent protein kinase (PKR) play a role in the antiviral responses as well as the regulation of cell function. We demonstrated the presence of PKR in FRTL-5 rat thyroid cells. Addition of dsRNA to FRTL-5 cells resulted in phosphorylation of eukaryotic initiation factor-2 and iκBα and induction of NFκB binding. In addition, type I IFN, especially IFN-β, and IRF-1 gene expression and STAT-1 phosphorylation were induced in dsRNA-stimulated cells. These results suggest that dsRNA activated signal transduction pathway may play a role in the regulation of thyroid function and may be involved in the pathogenesis of AITD.