title: Suppression of iodide uptake and thyroid hormone synthesis with stimulation of the type I interferon system by double-stranded ribonucleic acid in cultured human thyroid follicles.
abstract: Although viral infection is thought to be associated with subacute thyroiditis and probably with autoimmune thyroid disease, possible changes in thyroid function during the prodromal period of infection or subclinical infection remain largely unknown. Recently, it was shown that pathogen-associated molecular patterns stimulate Toll-like receptors (TLR) and activate innate immune responses by producing type I interferons (IFN). Using a human thyroid follicle culture system, in which de novo synthesized thyroid hormones are released into the culture medium under physiological concentrations of human TSH, we studied the effects of polyinosinic-polycytidylic acid [Poly(I:C)], a chemical analog of viral double-stranded RNA (dsRNA), on TSH-induced thyroid function. Thyrocytes expressed ligands for dsRNA (TLR 3, CD14, and retinoic-acid-inducible protein-1) comparable with the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3, IFN-beta, IFN-regulating factors, proinflammatory cytokines, and class I major histocompatibility complex (MHC), whereas genes associated with thyroid hormonogenesis (sodium/iodide symporter, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I:C) suppressed TSH-induced 125I uptake and hormone synthesis dose dependently, accompanied by a decrease in the ratio of 125I-T3/125I-T4 released into the culture medium, whereas peptidoglycan, lipopolysaccharides, or unmethylated CpG DNA, ligands for TLR2, TLR4, and TLR9, respectively, had no significant effect. These inhibitory effects of Poly(I:C) were not blocked by a neutralizing antibody against TLR3 and an anti-IFN alpha/beta receptor antibody. These in vitro findings suggest that when thyrocytes are infected with certain viruses, dsRNA formed intracellularly in thyrocytes may be a cause for thyroid dysfunction, leading to development of autoimmune thyroiditis.
authors: Thyroid Disease Institute, Kanaji Hospital, Tokyo, and Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, Japan.
authors: Kazuko
authors: K
authors: Yamazaki
authors: Koichi
authors: K
authors: Suzuki
authors: Emiko
authors: E
authors: Yamada
authors: Tetsu
authors: T
authors: Yamada
authors: Fumihiko
authors: F
authors: Takeshita
authors: Misako
authors: M
authors: Matsumoto
authors: Tomoaki
authors: T
authors: Mitsuhashi
authors: Takao
authors: T
authors: Obara
authors: Kazue
authors: K
authors: Takano
authors: Kanji
authors: K
authors: Sato
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D007454:Iodides / Q000378:metabolism / Q000493:pharmacokinetics*; D020411:Oligonucleotide Array Sequence Analysis; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013963:Thyroid Hormones / Q000096:biosynthesis*; D013972:Thyrotropin / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D007370:Interferon Type I; D016898:Interferon-alpha; D007454:Iodides; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D013963:Thyroid Hormones; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D016899:Interferon-beta; D013972:Thyrotropin