Thyroid Disease Institute, Kanaji Hospital, Tokyo, Japan.
Thyroid. 2010 Jan;20(1):67-76. doi: 10.1089/thy.2009.0242.
It is well known that iodide exacerbates thyroid function in subclinical hypothyroid patients with autoimmune thyroiditis. To investigate the immunological mechanism of iodine-induced thyroid dysfunction, we studied the effect of iodide in cultured human thyroid follicles, which respond to physiological concentrations of human thyrotropin (TSH) (0.3-10 microU/mL) and maintain the Wolff-Chaikoff effect.
Thyroid follicles obtained from Graves' patients at subtotal thyroidectomy were precultured in medium containing 0.5% fetal calf serum and 10(-8) M iodide for 5 days, and then cultured with the medium containing bovine TSH (30 microU/mL) and low (10(-8)M) or high (10(-5)M) concentrations of iodide. After 3-72 hours of culture, the effect of iodide on thyroid cell mRNA expression was analyzed by microarray and reverse transcriptase-polymerase chain reaction.
After 48 hours of culture, iodide nearly doubled the mRNA expression levels of the immunity-associated genes (intercellular adhesion molecule-1, transforming growth factor beta 1-induced protein, early growth response gene 1, guanylate-binding protein 1, and annexin A1) and decreased the mRNA expression of sodium-iodide symporter to less than 20%. Further, the mRNA expression levels of chemokines (CCL2, CXCL8, and CXCL14) increased nearly twofold, whereas their receptors did not show any significant response. Real-time polymerase chain reaction analyses confirmed that iodide increased the mRNA expression levels of these genes in a time- and concentration-dependent manner. Immunohistochemical studies revealed that the chemokines were expressed mainly in the thyroid follicular cells in addition to the immune cells. The iodide-induced increase in CCL2 was greater in thyroid follicles obtained from thyroid gland that had been moderately infiltrated with the immunocompetent cells.
We have demonstrated that iodide stimulates thyroid follicular cells to produce chemokines, particularly CCL2, CXCL8, and CXCL14. These chemokines and intercellular adhesion molecule-1 would attract immunocompetent cells into thyroid gland. These in vitro findings suggest that iodide at high concentrations may induce thyroid dysfunction through not only biochemical but also immunological mechanisms, particularly in patients with autoimmune thyroid disorders.
众所周知，碘会加剧自身免疫性甲状腺炎的亚临床甲状腺功能减退患者的甲状腺功能。为了研究碘诱导甲状腺功能障碍的免疫学机制，我们研究了碘在培养的人类甲状腺滤泡中的作用，这些滤泡对生理浓度的人促甲状腺激素（TSH）（0.3-10μU/mL）有反应，并维持沃尔夫-恰克效应。
从甲状腺次全切除术中获得的 Graves 患者的甲状腺滤泡在含有 0.5%胎牛血清和 10(-8)M 碘的培养基中预培养 5 天，然后用含有牛 TSH（30μU/mL）和低（10(-8)M）或高（10(-5)M）碘浓度的培养基培养。培养 3-72 小时后，通过微阵列和逆转录聚合酶链反应分析碘对甲状腺细胞 mRNA 表达的影响。
培养 48 小时后，碘几乎使免疫相关基因（细胞间黏附分子-1、转化生长因子β1 诱导蛋白、早期生长反应基因 1、鸟苷酸结合蛋白 1 和膜联蛋白 A1）的 mRNA 表达水平增加一倍，并使钠碘转运体的 mRNA 表达水平降低至低于 20%。此外，趋化因子（CCL2、CXCL8 和 CXCL14）的 mRNA 表达水平几乎增加了两倍，而其受体没有显示出任何显著的反应。实时聚合酶链反应分析证实，碘以时间和浓度依赖的方式增加这些基因的 mRNA 表达水平。免疫组织化学研究表明，除免疫细胞外，趋化因子主要在甲状腺滤泡细胞中表达。在免疫活性细胞中度浸润的甲状腺中获得的甲状腺滤泡中，CCL2 的碘诱导增加更大。
我们已经证明，碘刺激甲状腺滤泡细胞产生趋化因子，特别是 CCL2、CXCL8 和 CXCL14。这些趋化因子和细胞间黏附分子-1 将免疫活性细胞吸引到甲状腺中。这些体外发现表明，高浓度的碘可能不仅通过生化机制，而且通过免疫机制诱导甲状腺功能障碍，特别是在自身免疫性甲状腺疾病患者中。
