Zhu Xiaoxia, Chu Haiyan, Jiang Shuai, Liu Qingmei, Liu Lei, Xue Yu, Zheng Shucong, Wan Weiguo, Qiu Jianhua, Wang Jiucun, Zou Hejian
Division of Rheumatology, Huashan Hospital, Fudan University, China; Institute of Rheumatology, Immunology and Allergy, Fudan University, China.
Institute of Rheumatology, Immunology and Allergy, Fudan University, China; Ministry of Education (MOE) Key Laboratory of Contemporary, Anthropology and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
J Dermatol Sci. 2017 Aug;87(2):149-158. doi: 10.1016/j.jdermsci.2017.04.013. Epub 2017 May 3.
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation and fibrosis. Our previous research has indicated that Sirtuin1 (Sirt1) plays a role in the regulation of TNF-α-induced inflammation; however, whether Sirt1 may inhibit the progress of SSc by blocking inflammation remains unknown.
We aimed to investigate the function of Sirt1 in SSc.
The function and its mechanism of Sirt1 were evaluated in fibroblasts or scleroderma mice. The expression of Sirt1 and cytokines was analyzed using real-time PCR, western blot, ELISA and immunohistochemistry.
We determined that fibroblasts of SSc patients were activated to exhibit inflammation. Sirt1, activated by resveratrol (Res), ameliorated cutaneous inflammation and fibrosis in bleomycin (BLM)-induced scleroderma mice. An improvement in mammalian target of rapamycin (mTOR) was identified in the fibroblasts of SSc patients and the skin lesions of BLM mice. Rapamycin, an mTOR specific inhibitor, substantially inhibited the induced inflammation and fibrosis. The enhancement of mTOR expression in the skin lesions of the BLM-treated mice was significantly inhibited by Sirt1 activation. However, in both the BLM-treated cells and mice, Res exerted an inhibitory function on the expression of inflammatory factors, and collagen was diminished following mTOR knockdown. These findings suggest that Res may inhibit inflammation and fibrosis via mTOR.
The modulation of Sirt1 activity may represent a potential therapeutic method for SSc. The mechanism may involve the inhibition of mTOR phosphorylation, whereas mTOR activity was shown to be a pathogenic culprit of SSc.
系统性硬化症（SSc）是一种以炎症和纤维化为特征的慢性自身免疫性疾病。我们之前的研究表明，沉默调节蛋白1（Sirt1）在肿瘤坏死因子-α诱导的炎症调节中发挥作用；然而，Sirt1是否可通过阻断炎症来抑制SSc的进展仍不清楚。
我们旨在研究Sirt1在SSc中的作用。
在成纤维细胞或硬皮病小鼠中评估Sirt1的功能及其机制。使用实时聚合酶链反应、蛋白质免疫印迹法、酶联免疫吸附测定和免疫组织化学分析Sirt1和细胞因子的表达。
我们确定SSc患者的成纤维细胞被激活以表现出炎症。白藜芦醇（Res）激活的Sirt1改善了博来霉素（BLM）诱导的硬皮病小鼠的皮肤炎症和纤维化。在SSc患者的成纤维细胞和BLM小鼠的皮肤病变中发现雷帕霉素靶蛋白（mTOR）有所改善。雷帕霉素是一种mTOR特异性抑制剂，可显著抑制诱导的炎症和纤维化。Sirt1激活可显著抑制BLM处理小鼠皮肤病变中mTOR表达的增强。然而，在BLM处理的细胞和小鼠中，Res均对炎症因子的表达发挥抑制作用，并且在mTOR敲低后胶原蛋白减少。这些发现表明，Res可能通过mTOR抑制炎症和纤维化。
调节Sirt1活性可能是SSc的一种潜在治疗方法。其机制可能涉及抑制mTOR磷酸化，而mTOR活性被证明是SSc的致病因素。
