RESUMO
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 H(2)O(2) produced by IFN-gamma treatment in thyroid cells and thus inhibits the H(2)O(2)-mediated phosphorylation of tyrosine 701 in STAT1. MMI also eliminates H(2)O(2) in vitro. MMI facilitates electron transfer from NADPH to H(2)O(2) using thioredoxin or glutathione, fulfilling a role similar to peroxiredoxin or glutathione peroxidase, respectively. MMI prevents the IFN-gamma and H(2)O(2)-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.
Assuntos
Antioxidantes/farmacologia , Expressão Gênica/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Interferon gama/farmacologia , Metimazol/farmacologia , Proteínas , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Glândula Tireoide/efeitos dos fármacos , Fatores de Transcrição , Adjuvantes Imunológicos/farmacologia , Animais , Proteínas de Transporte/biossíntese , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Interações Medicamentosas , Transporte de Elétrons/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/genética , Interferon gama/antagonistas & inibidores , Janus Quinase 1 , Janus Quinase 2 , Cinética , Peroxidases/farmacologia , Peroxirredoxinas , Fosforilação/efeitos dos fármacos , Biossíntese de Proteínas , Proteínas Inibidoras de STAT Ativados , Proteínas Tirosina Quinases/metabolismo , Ratos , Fator de Transcrição STAT1 , Fator de Transcrição STAT3 , Transdução de Sinais/fisiologia , Proteína 1 Supressora da Sinalização de Citocina , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina , Glândula Tireoide/citologia , Glândula Tireoide/metabolismo , Transativadores/metabolismo , Tirosina/metabolismoRESUMO
We isolated a cDNA representing a message that was strongly induced by injection with E. coli in Bombyx mori. The 2160 bp cDNA has an open reading frame of 644 amino acids and the deduced product a predicted molecular mass of 71 kDa. The cDNA sequence shared high homology with the transferrins known so far, and its deduced peptide had unique features of transferrins, that is, sites of cystein residues and iron binding. We suggest that the B. mori transferrin plays an important role in the self-defense system.