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

近年来的研究表明，病原体相关分子模式(PAMPS)通过产生I型干扰素(I型干扰素)刺激Toll样受体(TLR)，激活天然免疫反应。利用人甲状腺滤泡培养系统，在生理浓度的HTSH作用下，将合成的甲状腺激素释放到培养液中，研究了病毒双链RNA(DsRNA)的化学类似物聚肌苷多胞苷(Poly(I：C))对TSH诱导的甲状腺功能的影响。我们发现，甲状腺细胞表达与TSH受体类似的dsRNA配体(TLR3、CD14和RIG-1)。基因芯片和实时定量聚合酶链式反应分析显示，双链RNA上调TLR3、干扰素-β、干扰素调节因子、促炎性细胞因子和I类MHC的基因表达，而抑制与甲状腺激素生成相关的基因(NIS、过氧化物酶、脱碘酶)的表达。根据这些数据，Poly(I：C)抑制促甲状腺激素诱导的I摄取和…更多的激素合成呈剂量依赖关系，伴随着释放到培养基中的^&lt；125&gt；i-t3/^&lt；i-t4比率的降低。这些体外研究结果表明，当甲状腺细胞感染某些病毒时，细胞内形成的dsRNA可能是甲状腺功能障碍的原因，导致自身免疫性甲状腺炎的发生(参考文献3)。众所周知，无机碘用于甲亢患者(如Graves病)时，会减少甲状腺血流量。为了阐明这一机制，我们研究了无机碘对保留Wolff-Chaikoff效应的培养的人甲状腺滤泡中血管内皮生长因子家族的影响。利用可以分析全人类基因(多达41,000个基因点)的寡核苷酸芯片，我们发现高浓度的碘降低了血管内皮生长因子A、B和胎盘生长因子的mRNA表达水平，增加了从血浆中产生血管抑素的尿激酶型纤溶酶原激活物。这些数据表明，碘通过抑制血管生成因子的产生和刺激血管生成抑制物的产生来减少甲状腺的血流量(参考文献1)。较少

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