Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.
Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.
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DOI：
10.1371/journal.pone.0007857
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发表时间：
2009-11-17
期刊：
影响因子：
3.7
通讯作者：
Caturegli P
中科院分区：
文献类型：
--
作者：
Kimura HJ;Chen CY;Tzou SC;Rocchi R;Landek-Salgado MA;Suzuki K;Kimura M;Rose NR;Caturegli P
甲状腺癌细胞（Hürthle细胞）存在于肿瘤和自身免疫性疾病中。它们有一个独特的外观特点是丰富的颗粒状嗜酸性细胞质和深染核。其发病机制至今仍不清楚。使用在甲状腺中长期表达IFNγ的转基因小鼠，我们发现甲状腺滤泡上皮发生了类似于人类肿瘤细胞的变化。比较转基因与野生型甲状腺细胞的转录组分析显示，转基因中免疫蛋白酶体亚基如LMP2的水平增加，表明免疫蛋白酶体在肿瘤细胞发病机制中的重要作用。事实上，蛋白酶体的药理学阻断改善了嗜酸性细胞表型。LMP2亚基的基因缺失可以防止嗜酸细胞表型和原发性甲状腺功能减退症的发生。LMP2也在桥本甲状腺炎和Hürthle细胞瘤患者的癌细胞中表达。总之，我们报告说，嗜酸细胞的免疫蛋白酶体表达增加继发于慢性炎症环境的结果，并建议LMP2作为一种新的治疗靶点，用于治疗嗜酸细胞病变和自身免疫性甲状腺功能减退症。
Oncocytes of the thyroid gland (Hürthle cells) are found in tumors and autoimmune diseases. They have a unique appearance characterized by abundant granular eosinophilic cytoplasm and hyperchromatic nucleus. Their pathogenesis has remained, thus far, unknown. Using transgenic mice chronically expressing IFNγ in thyroid gland, we showed changes in the thyroid follicular epithelium reminiscent of the human oncocyte. Transcriptome analysis comparing transgenic to wild type thyrocytes revealed increased levels of immunoproteasome subunits like LMP2 in transgenics, suggesting an important role of the immunoproteasome in oncocyte pathogenesis. Pharmacologic blockade of the proteasome, in fact, ameliorated the oncocytic phenotype. Genetic deletion of LMP2 subunit prevented the development of the oncocytic phenotype and primary hypothyroidism. LMP2 was also found expressed in oncocytes from patients with Hashimoto thyroiditis and Hürthle cell tumors. In summary, we report that oncocytes are the result of an increased immunoproteasome expression secondary to a chronic inflammatory milieu, and suggest LMP2 as a novel therapeutic target for the treatment of oncocytic lesions and autoimmune hypothyroidism.
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影响因子：
3.6
作者：
Hu, GQ;Lin, G;Li, HL
通讯作者：
Li, HL
影响因子：
13.6
作者：
Chade, AR;Herrmann, J;Lerman, LO
通讯作者：
Lerman, LO
DOI：
10.1084/jem.187.1.97
发表时间：
1998-01-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Griffin TA;Nandi D;Cruz M;Fehling HJ;Kaer LV;Monaco JJ;Colbert RA
通讯作者：
Colbert RA
影响因子：
4.6
作者：
AuBuchon, J. P.;de Wildt-Eggen, J.;Dumont, L. J.
通讯作者：
Dumont, L. J.
影响因子：
5.4
作者：
Fissolo, Nicolas;Kraus, Marianne;Weissert, Robert
通讯作者：
Weissert, Robert