STAT6 blockade ameliorates thyroid function in Graves’ disease via downregulation of the sodium/iodide symporter

Background: Signal transducer and activator of transcription 6 (STAT6) is a critical nuclear transcription factor. Previous studies have shown that inhibiting STAT6 can improve thyroid function by lowering serum levels of T3 and T4. The sodium/iodide symporter (NIS), a key protein responsible for active iodine uptake, plays a vital role in regulating thyroid function. This study investigates the interaction between STAT6 and NIS.

Methods: Immunohistochemical staining was used to assess NIS expression across different tissues. Reverse transcription-polymerase chain reaction (RT-PCR) measured NIS mRNA levels in Nthy-ori 3-1 cells treated with IL-4, thyroid-stimulating hormone (TSH), or thyroid-specific stimulatory autoantibody (TSAb) for 24 hours. Quantitative RT-PCR, Western blot, and immunofluorescence analysis were performed to evaluate NIS expression after blocking STAT6 phosphorylation using AS1517499. Finally, luciferase reporter assays assessed the effect of STAT6 on the promoter activity of the NIS gene.

Results: NIS was highly expressed in the thyroid epithelial cells of experimental autoimmune Graves’ disease (EAGD) mice and in patients with Graves’ disease (GD). TSAb treatment elevated NIS expression. Blocking STAT6 phosphorylation with AS1517499 mitigated the TSAb-induced increase in NIS protein and mRNA levels. Additionally, the transcription factor STAT6 was confirmed to regulate NIS transcription, with the co-activator P100 enhancing STAT6-mediated transcriptional activation.

Conclusion: In Graves’ disease, TSAb activates STAT6 signaling, leading to increased NIS expression. Blocking STAT6 improves thyroid function by reducing NIS levels. This study provides new insights into STAT6′s role in thyroid regulation and suggests potential therapeutic strategies for treating GD.