Abstract

The antithyroid drug, methimazole (MMI) is used to treat patients with Graves' hyperthyroidism. The major action of MMI is to inhibit synthesis of thyroid hormone in the thyroid gland. However, MMI also has antioxidant and immunomodulatory effects on thyrocytes and/or immune cells. This study identifies novel antioxidant and immunomodulatory effects of MMI involving the interferon-γ (IFN-γ) signaling pathway in thyroid cells. MMI inhibits transcription of the intercellular adhesion molecule-1 (ICAM-1) gene by modulating the function of transcription factor STAT1 (signal transducer and activator of transcription 1), which binds to the IFN-γ activated site of the ICAM-1 promoter. Furthermore, MMI rapidly eliminates H₂O₂ produced by IFN-γ treatment in thyroid cells and thus inhibits the H₂O₂-mediated phosphorylation of tyrosine 701 in STAT1. MMI also eliminates H₂O₂in vitro. MMI facilitates electron transfer from NADPH to H₂O₂ using thioredoxin or glutathione, fulfilling a role similar to peroxiredoxin or glutathione peroxidase, respectively. MMI prevents the IFN-γ and H₂O₂-mediated reversible inactivation of phosphatases. These effects inhibit full activation of the IFN-γ-induced Janus kinase(JAK)/STAT signaling pathway in FRTL-5 thyroid cells. These results may in part explain the antioxidant and immunomodulatory effects of MMI in thyroid cells of Graves' disease patients.