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(IRF-1)是一种干扰素诱导的转录因子，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(AITD)的发病机制。为探讨IRF-1在AITD发生发展中的作用，对非肥胖型糖尿病(NOD)小鼠甲状腺炎症的发生率和严重程度进行了研究。在摄入IRF-1+/+和+/-的14周龄小鼠中，超过80%的小鼠发生淋巴细胞性甲状腺炎(LT)，而没有摄入IRF-1+/-的小鼠发生淋巴细胞性甲状腺炎(LT)。相比之下，24周龄的小鼠和甲状腺球蛋白(TG)免疫的小鼠发生了甲状腺炎，与IRF-1无关。在后者中，甲状腺炎症的严重程度没有显著差异。在IRF1-/-小鼠中，脾中CD8+T细胞和干扰素-γ的分泌减少。这些结果提示CD8+T细胞和Th1反应参与了IRF-1缺陷NOD小鼠碘诱导LT的发生。然而，NOD小鼠自发性和甘油三酯诱导的甲状腺炎可能涉及不同的机制。[PKR研究]双链RNA(DsRNA)依赖的蛋白激酶(PKR)在抗病毒反应和细胞功能调节中发挥作用。我们证实了FRTL-5大鼠甲状腺细胞中存在PKR。在FRTL5细胞中加入双链RNA可使真核细胞起始因子2和IκBα磷酸化，并诱导核转录因子κB结合。此外，在双链RNA刺激的细胞中，诱导了I型干扰素，尤其是干扰素-β，以及IRF-1基因的表达和STAT-1的磷酸化。提示dsRNA激活的信号转导通路可能参与了甲状腺功能的调节，并可能参与了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.