IGF-1 upregulates IL-36α expression via NF-κB and p38 MAPK pathways to promote inflammation in thyroid eye disease

Thyroid eye disease (TED), the most prevalent extrathyroidal manifestation of Graves' disease, involves insulin-like growth factor-1 (IGF-1) as a central pathogenic factor. Interleukin-36α (IL-36α), a key member of the IL-1 superfamily, has emerged as a critical regulator in autoimmune diseases.

To investigate the role of IL-36α in TED pathogenesis and elucidate the molecular mechanisms by which IGF-1 regulates IL-36α expression.

Specimens including serum and orbital connective tissues were obtained from TED subjects and controls. Orbital fibroblasts (OFs) were isolated from patients with TED. Enzyme-linked immunosorbent assay, immunohistochemistry, quantitative real-time PCR and Western blot analysis were performed.

We demonstrated that IL-36α levels increased in the circulation and orbital connective tissues of patients with TED compared with controls, and levels were positively correlated with the clinical activity score. In vitro, IGF-1 induced IL-36α expression in OFs through NF-κB and p38 MAPK pathway activation. Furthermore, we revealed that IL-36α stimulation promoted robust pro-inflammatory cytokine production, which was effectively blocked by Interleukin-36 receptor antagonist (IL-36Ra) treatment.

IGF-1 upregulates IL-36α expression via NF-κB and p38 MAPK pathways to promote inflammation in TED, with IL-36α levels significantly correlating with disease activity. These findings identify IL-36α as a promising biomarker and therapeutic target for TED management.