Graves’ ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves’ disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue () and serum specimens () obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.

中文翻译：

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辛伐他汀通过调节 FoxO3a 信号抑制 Graves 眼病眼眶成纤维细胞 CYR61 的表达

Graves 眼病 (GO) 以眼眶组织炎症、扩张和纤维化为特征，是 25% 至 50% 的 Graves 病患者的眼部表现。由于 GO 的病理是由自身免疫性炎症驱动的，许多促炎细胞因子/趋化因子，包括 TNF - α、IL- 1β、IL-6 和 CCL20 在 GO 的发病机制中至关重要，可激活眼眶成纤维细胞。富含半胱氨酸的蛋白 61 (CYR61)，已知可调节细胞增殖、粘附和迁移，在许多炎症性疾病（如类风湿性关节炎）的发病机制中发挥促炎作用。在最近的研究中，CYR61 被认为是 GO 的潜在生物标志物。他汀类药物是降低胆固醇的药物，被发现可以降低 GO 的风险，这可能是通过它们的抗炎和免疫调节作用。在这项研究中，我们在 GO 的发病机制和潜在治疗中建立了 CYR61 和他汀类药物之间的联系。首先，我们的数据显示眼眶组织中 CYR61 过表达（)和血清标本 ()来自非活动性 GO 的患者。CYR61 可以诱导培养的 GO 眼眶成纤维细胞产生 IL-6 和 CCL20。CYR61 在培养的 GO 眼眶成纤维细胞中的表达通过 TNF- α刺激上调。其次，我们使用辛伐他汀（一种他汀类药物）预处理培养的 GO 眼眶成纤维细胞，然后使用 TNF- α刺激。数据显示，辛伐他汀可以通过调节转录因子 FoxO3a 的活性来抑制 TNF- α诱导的 CYR61 表达。我们的结果提供了对一些细胞机制的见解，这些机制可以解释辛伐他汀对 GO 发展的可能保护作用。