Gianoukakis Andrew G, Jennings Timothy A, King Chris S, Sheehan Christine E, Hoa Neil, Heldin Paraskevi, Smith Terry J
Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California 90502, USA.
Endocrinology. 2007 Jan;148(1):54-62. doi: 10.1210/en.2006-0736. Epub 2006 Oct 26.
Graves' disease (GD) and Hashimoto's thyroiditis (HT) are autoimmune processes often associated with hyperthyroidism and hypothyroidism, respectively. Despite their diverging clinical presentations, immune activation drives both diseases and results in connective tissue accumulation of the nonsulfated glycosaminoglycan, hyaluronan. The hydrophilic property of hyaluronan contributes to the pathogenesis of thyroid-associated ophthalmopathy, dermopathy and hypothyroid myxedema. Whether hyaluronan accumulates in the thyroid and plays a role in goiter formation in GD and HT remains unknown. We report here that levels of hyaluronan are increased in thyroid tissue from individuals with both diseases compared with glands uninvolved with autoimmune disorders. The transcript encoding hyaluronan synthase (HAS)-3, one of three mammalian HAS isoforms, was detected in thyroid tissue. Isolated thyrocytes in primary culture express all three HAS isoforms when treated with IL-1beta. Thyrocytes and thyroid fibroblasts produce hyaluronan under basal culture conditions and IL-1beta enhances levels of this molecule in both cell types. On a per-cell basis, fibroblasts produce more hyaluronan than do thyrocytes under basal conditions and after cytokine treatment. Synthesis in thyrocytes can also be altered by increasing serum concentration in the medium and by modifying culture density. Our findings suggest that hyaluronan accumulation in thyroid tissue might derive from thyrocytes and fibroblasts. Moreover, this glycosaminoglycan becomes more abundant as a consequence of autoimmune disease. It may therefore contribute to increased thyroid volume in GD and HT. Coupled with the newly identified influence exerted by hyaluronan on immunocompetent cells, our findings represent potentially important insights into the pathogenesis of autoimmune thyroid diseases.
格雷夫斯病（GD）和桥本甲状腺炎（HT）是自身免疫性疾病，通常分别与甲状腺功能亢进和甲状腺功能减退相关。尽管它们的临床表现不同，但免疫激活驱动这两种疾病，并导致非硫酸化糖胺聚糖透明质酸在结缔组织中积累。透明质酸的亲水性有助于甲状腺相关性眼病、皮肤病和甲状腺功能减退性黏液水肿的发病机制。透明质酸是否在甲状腺中积累并在GD和HT的甲状腺肿形成中起作用仍不清楚。我们在此报告，与未患自身免疫性疾病的腺体相比，这两种疾病患者的甲状腺组织中透明质酸水平升高。在甲状腺组织中检测到编码透明质酸合酶（HAS）-3的转录本，HAS-3是三种哺乳动物HAS同工型之一。原代培养中分离的甲状腺细胞在接受白细胞介素-1β处理时表达所有三种HAS同工型。甲状腺细胞和甲状腺成纤维细胞在基础培养条件下产生透明质酸，白细胞介素-1β可提高这两种细胞类型中该分子的水平。在基础条件下和细胞因子处理后，成纤维细胞在每个细胞基础上产生的透明质酸比甲状腺细胞更多。甲状腺细胞中的合成也可通过增加培养基中的血清浓度和改变培养密度来改变。我们的研究结果表明，甲状腺组织中透明质酸的积累可能源自甲状腺细胞和成纤维细胞。此外，由于自身免疫性疾病，这种糖胺聚糖变得更加丰富。因此，它可能导致GD和HT中甲状腺体积增加。再加上最近发现透明质酸对免疫活性细胞有影响，我们的研究结果代表了对自身免疫性甲状腺疾病发病机制的潜在重要见解。
