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Vol. 60, Issue 5, 972-980, November 2001

Methimazole As an Antioxidant and Immunomodulator in Thyroid Cells: Mechanisms Involving Interferon-gamma Signaling and H2O2 Scavenging

Ho Kim, Tae-Hoon Lee, Young Sun Hwang, Mi Ae Bang, Kang Hwa Kim, Jae Mi Suh, Hyo Kyun Chung, Dae-Yeul Yu, Kyung-Kwang Lee, O-Yu Kwon, Heung Kyu Ro, and Minho Shong

Department of Internal Medicine (S.H.K., J.M.S., H.K.C., H.K.R., M.S.), Department of Anatomy (O.-Y.K.), Chungnam National University, Taejon, Korea; Korea Research Institute of Bioscience and Biotechnology (Y.-H.L., D.-Y.Y., K.-K.L.), Yusong, Taejon, Korea; and Department of Food and Nutrition, College of Home Economics (Y.S.H., M.A.B., K.H.K.), Chonnam National University, Kwang-Ju, Korea

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-gamma (IFN-gamma ) 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-gamma activated site of the ICAM-1 promoter. Furthermore, MMI rapidly eliminates H2O2 produced by IFN-gamma treatment in thyroid cells and thus inhibits the H2O2-mediated phosphorylation of tyrosine 701 in STAT1. MMI also eliminates H2O2 in 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-gamma and H2O2-mediated reversible inactivation of phosphatases. These effects inhibit full activation of the IFN-gamma -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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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