Yang Qian, Zhang Qinnan, Pan Fanfan, Zha Bingbing
Department of Endocrinology, Fifth People's Hospital of Shanghai Fudan University, Shanghai, China.
Center of Community-Based Health Research, Fudan University, Shanghai, China.
Endocr Connect. 2024 Nov 22;13(12). doi: 10.1530/EC-24-0428. Print 2024 Dec 1.
Signal transducer and activator of transcription 6 (STAT6) is an important nuclear transcription factor. Previous studies demonstrated that blocking STAT6 can ameliorate thyroid function by reducing serum T3 and T4. Sodium/iodide symporter (NIS) is a key protein that mediates active iodine uptake and plays an important role in regulating thyroid function. This study explored the interaction between STAT6 and NIS.
Immunohistochemical staining was performed for detecting the expression of NIS in different tissues. RT-PCR was performed for evaluating the mRNA level of NIS when Nthy-ori 3-1 cells were incubated with IL4, thyroid stimulating hormone (TSH), or monoclonal thyroid-specific stimulatory autoantibody (TSAb) for 24 h. Quantitative RT-PCR, western blot, and immunofluorescence analysis were performed for detecting NIS expression after inhibiting STAT6 phosphorylation by AS1517499. Finally, we used luciferase reporter assays to explore the ability of STAT6 to regulate the promoter activity of the NIS-coding gene.
NIS was highly expressed in thyroid epithelial cells of EAGD mice or Graves' disease (GD) patients, and TSAb increased the expression of NIS. We show that a STAT6 phosphorylation inhibitor can attenuate the effect of TSAb on increasing NIS protein and mRNA levels. Finally, we confirm that transcription factor STAT6 can mediate NIS transcription and co-activator P100 protein can enhance STAT6-dependent transcriptional activation.
In GD, TSAb induces STAT6 signaling to upregulate NIS expression, and STAT6 blockade ameliorates thyroid function via downregulation of the NIS. Our study furthers understanding of the effects of STAT6 on thyroid function and reveals new avenues for GD treatment.
信号转导与转录激活因子6（STAT6）是一种重要的核转录因子。先前的研究表明，阻断STAT6可通过降低血清T3和T4来改善甲状腺功能。钠/碘同向转运体（NIS）是介导碘主动摄取的关键蛋白，在调节甲状腺功能中起重要作用。本研究探讨了STAT6与NIS之间的相互作用。
采用免疫组织化学染色检测不同组织中NIS的表达。当Nthy-ori 3-1细胞分别与IL4、促甲状腺激素（TSH）或单克隆甲状腺特异性刺激自身抗体（TSAb）孵育24小时后，采用RT-PCR评估NIS的mRNA水平。通过AS1517499抑制STAT6磷酸化后，进行定量RT-PCR、蛋白质印迹和免疫荧光分析以检测NIS表达。最后，我们使用荧光素酶报告基因检测来探索STAT6调节NIS编码基因启动子活性的能力。
NIS在EAGD小鼠或格雷夫斯病（GD）患者的甲状腺上皮细胞中高表达，且TSAb可增加NIS的表达。我们发现STAT6磷酸化抑制剂可减弱TSAb对增加NIS蛋白和mRNA水平的作用。最后，我们证实转录因子STAT6可介导NIS转录，且共激活因子P100蛋白可增强STAT6依赖性转录激活。
在GD中，TSAb诱导STAT6信号传导以上调NIS表达，而阻断STAT6可通过下调NIS来改善甲状腺功能。我们的研究进一步加深了对STAT6对甲状腺功能影响的理解，并揭示了GD治疗的新途径。
