Human fibrocytes coexpress thyroglobulin and thyrotropin receptor
Human fibrocytes coexpress thyroglobulin and thyrotropin receptor
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DOI：
10.1073/pnas.1202064109
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发表时间：
2012-05-08
影响因子：
11.1
通讯作者：
Smith, Terry J.
中科院分区：
文献类型：
--
作者：
Fernando, Roshini;Atkins, Stephen;Smith, Terry J.
甲状腺球蛋白（Tg）是甲状腺激素的大分子前体，被认为是甲状腺上皮细胞唯一表达的。Tg和促甲状腺激素受体（TSHR）是自身免疫性疾病Graves病（GD）中自身抗体产生的靶点。完全表达的GD以甲状腺过度活跃和眼眶组织炎症和重塑为特征。这个过程被称为甲状腺相关性眼病（TAO）。早期的报道表明，在TAO中，Tg和TSHR在眼眶组织中都过度表达。之前，我们发现CD34（+）祖细胞，被称为纤维细胞，表达功能性TSHR，浸润眼眶，并构成TAO眼眶成纤维细胞的一个大子集。我们现在报道纤维细胞也表达Tg，它在Western blots上分解为305 kda蛋白。此外，（125）碘和[S-35]蛋氨酸被纳入纤维细胞表达的Tg中。通过靶向蛋白质的特异性小干扰RNA，可以减弱从头合成Tg。Tg基因启动子片段融合到荧光素酶报告基因中，转染到纤维细胞后显示出大量的活性。与纤维细胞不同，GD轨道成纤维细胞包含CD34（+）和CD34（-）细胞的混合物，表达的Tg和TSHR水平要低得多。当被分为纯CD34（+）和CD34（-）亚群时，Tg和TSHR mRNA水平在CD34（+）细胞中显著升高。这些发现表明，人类纤维细胞表达多种“甲状腺特异性”蛋白，其水平在浸润组织后降低。我们的观察为GD轨道上的Tg积累奠定了基础。
Thyroglobulin (Tg) is the macromolecular precursor of thyroid hormones and is thought to be uniquely expressed by thyroid epithelial cells. Tg and the thyroid-stimulating hormone receptor (TSHR) are targets for autoantibody generation in the autoimmune disorder Graves disease (GD). Fully expressed GD is characterized by thyroid overactivity and orbital tissue inflammation and remodeling. This process is known as thyroid-associated ophthalmopathy (TAO). Early reports suggested that in TAO, both Tg and TSHR become overexpressed in orbital tissues. Previously, we found that CD34(+) progenitor cells, known as fibrocytes, express functional TSHR, infiltrate the orbit, and comprise a large subset of orbital fibroblasts in TAO. We now report that fibrocytes also express Tg, which resolves as a 305-kDa protein on Western blots. It can be immunoprecipitated with anti-Tg Abs. Further, (125)iodine and [S-35]methionine are incorporated into Tg expressed by fibrocytes. De novo Tg synthesis is attenuated with a specific small interfering RNA targeting the protein. A fragment of the Tg gene promoter fused to a luciferase reporter exhibits substantial activity when transfected into fibrocytes. Unlike fibrocytes, GD orbital fibroblasts, which comprise a mixture of CD34(+) and CD34(-) cells, express much lower levels of Tg and TSHR. When sorted into pure CD34(+) and CD34(-) subsets, Tg and TSHR mRNA levels become substantially higher in CD34(+) cells. These findings indicate that human fibrocytes express multiple "thyroid-specific" proteins, the levels of which are reduced after they infiltrate tissue. Our observations establish the basis for Tg accumulation in orbital GD.