STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia
STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia
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STAT6缺陷通过抑制甲状腺上皮细胞增生来改善格雷夫斯病的严重程度
DOI：
10.1038/cddis.2016.398
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发表时间：
2016-12-01
影响因子：
9
通讯作者：
Chu, Yiwei
中科院分区：
文献类型：
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作者：
Jiang, Xuechao;Zha, Bingbing;Chu, Yiwei
信号转导子和转录激活子6（STAT 6）参与上皮细胞生长。然而，关于STAT 6在Graves病（GD）中的磷酸化状态及其在甲状腺上皮细胞（TEC）中的作用知之甚少。在这项研究中，我们发现，STAT 6磷酸化（p-STAT 6）显着增加的TEC从GD患者和实验性自身免疫性Graves病小鼠和STAT 6缺陷改善GD症状。TEC中的自分泌IL-4信号通过IL-4 R接合激活STAT 6的磷酸化，并且STAT 6的下游靶点是Bcl-xL和细胞周期蛋白D1。因此，IL-4-STAT 6-Bcl-xL/细胞周期蛋白D1通路对于TEC增生是至关重要的，TEC增生使GD恶化。更重要的是，体外和体内实验表明，AS 1517499抑制STAT 6磷酸化可减少TEC增生，从而降低血清T3和T4，改善GD。因此，我们的研究表明，除了GD的传统发病机制，其中自身抗体TRAb刺激促甲状腺激素受体，从而产生T3，T4，TRAb也可以触发TEC产生IL-4，然后IL-4以自分泌方式激活p-STAT 6信号传导并刺激细胞无限制生长，从而加重GD。这些发现表明，STAT 6抑制剂可能是治疗GD的有效疗法。
Signal transducer and activator of transcription 6 (STAT6) is involved in epithelial cell growth. However, little is known regarding the STAT6 phosphorylation status in Graves' disease (GD) and its role in thyroid epithelial cells (TECs). In this study, we found that STAT6 phosphorylation (p-STAT6) was significantly increased in TECs from both GD patients and experimental autoimmune Graves' disease mice and that STAT6 deficiency ameliorated GD symptoms. Autocrine IL-4 signalling in TECs activated the phosphorylation of STAT6 via IL-4 R engagement, and the downstream targets of STAT6 were Bcl-xL and cyclin D1. Thus, the IL-4-STAT6-Bcl-xL/cyclin D1 pathway is crucial for TEC hyperplasia, which aggravates GD. More importantly, in vitro and in vivo experiments demonstrated that STAT6 phosphorylation inhibited by AS1517499 decreased TEC hyperplasia, thereby reducing serum T3 and T4 and ameliorating GD. Thus, our study reveals that in addition to the traditional pathogenesis of GD, in which autoantibody TRAb stimulates thyroid-stimulating hormone receptors and consequently produces T3, T4, TRAb could also trigger TECs producing IL-4, and IL-4 then acts in an autocrine manner to activate p-STAT6 signalling and stimulate unrestricted cell growth, thus aggravating GD. These findings suggest that STAT6 inhibitors could be potent therapeutics for treating GD.