STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia

Area of Science:

• Endocrinology
• Molecular Biology
• Immunology

Background:

• Signal transducer and activator of transcription 6 (STAT6) regulates epithelial cell growth.
• The role of STAT6 phosphorylation in Graves' disease (GD) and thyroid epithelial cells (TECs) is largely unknown.

Purpose of the Study:

• To investigate the STAT6 phosphorylation status in TECs from GD patients.
• To elucidate the role of the IL-4-STAT6 pathway in TEC hyperplasia and GD pathogenesis.
• To evaluate the therapeutic potential of STAT6 inhibition in GD.

Main Methods:

• Assessed STAT6 phosphorylation (p-STAT6) in TECs from GD patients and experimental autoimmune GD mice.
• Investigated the IL-4-STAT6 signaling pathway and its downstream targets (Bcl-xL, cyclin D1).
• Utilized in vitro and in vivo models to test the efficacy of the STAT6 inhibitor AS1517499.

Main Results:

• p-STAT6 levels were significantly elevated in TECs from GD patients and mice.
• STAT6 deficiency ameliorated GD symptoms.
• The IL-4-STAT6-Bcl-xL/cyclin D1 pathway was identified as crucial for TEC hyperplasia in GD.
• AS1517499 treatment reduced TEC hyperplasia, lowered serum T3 and T4 levels, and ameliorated GD.

Conclusions:

• TRAb can trigger IL-4 production in TECs, activating autocrine p-STAT6 signaling and promoting TEC hyperplasia, thus aggravating GD.
• STAT6 plays a critical role in GD pathogenesis beyond traditional mechanisms.
• STAT6 inhibitors represent a promising therapeutic strategy for treating Graves' disease.