Endocrinological and Immunological Roles of Toll-like Receptor 3 in Culture Human Thyroid Follicles

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Recently, it was shown that pathogen-associated molecular patterns (PAMPS) 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 hTSH, 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.We found that thyrocytes expressed ligands for dsRNA (TLR3, CD14, and RIG-1) comparable to the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3,IFN-β, interferon-regulating factors, proinflammatory cytokines, and class I MHC, whereas genes associated with thyroid hormonogenesis (NIS, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I : C) suppressed TSH-induced ^<125>I uptake and … More hormone synthesis dose-dependently, accompanied by a decrease in the ratio of ^<125>I-T3/^<125>I-T4 released into the culture medium. 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 (Reference 3).It is well known that inorganic iodide, when administered to hyperthyroid patients such as Graves' disease, decreases a thyroidal blood flow. To elucidate this mechanism, we studied the effects of inorganic iodide on vascular endothelial growth factor families in cultured human thyroid follicles in which Wolff-Chaikoff effect was well preserved. Using oligo-microarray which can analyze whole human genes (up to 41,000 gene spots), we found that iodide at high concentration decreased mRNA expression level of VEGF-A, VEGF-B and Placental growth factors, and increased urokinase-type plasminogen activator that produces angiostatin from plasmin.These data suggest that iodide reduces a thyroidal blood flow by inhibiting the production of angiogenesis factors and stimulating the production of angiogenesis inhibitors (Reference 1). Less