de Seabra Rodrigues Dias Ivo R, Mok Simon W F, Gordillo-Martínez Flora, Khan Imran, Hsiao Wendy W L, Law Betty Y K, Wong Vincent K W, Liu Liang
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
Front Pharmacol. 2018 Jan 8;8:962. doi: 10.3389/fphar.2017.00962. eCollection 2017.
Rheumatoid arthritis synovial fibroblasts (RASFs) are fundamental effector cells in RA driving the joint inflammation and deformities. Celastrol is a natural compound that exhibits a potent anti-arthritic effect promoting endoplasmic reticulum (ER) stress mediated by intracellular calcium (Ca) mobilization. Ca is a second messenger regulating a variety of cellular processes. We hypothesized that the compound, celastrol, affecting cytosolic Ca mobilization could serve as a novel strategy to combat RA. To address this issue, celastrol was used as a molecular tool to assay the inflammatory gene expression profile regulated by Ca. We confirmed that celastrol treatment mobilized cytosolic Ca in patient-derived RASFs. It was found that 23 genes out of 370 were manipulated by Ca mobilization using an inflammatory and autoimmunity PCR array following independent quantitative PCR validation. Most of the identified genes were downregulated and categorized into five groups corresponding to their cellular responses participating in RA pathogenesis. Accordingly, a signaling network map demonstrating the possible molecular circuitry connecting the functions of the products of these genes was generated based on literature review. In addition, a bioinformatics analysis revealed that celastrol-induced Ca mobilization gene expression profile showed a novel mode of action compared with three FDA-approved rheumatic drugs (methotrexate, rituximab and tocilizumab). To the best of our knowledge, this is a pioneer work charting the Ca signaling network on the regulation of RA-associated inflammatory gene expression.
类风湿性关节炎滑膜成纤维细胞（RASFs）是类风湿性关节炎中驱动关节炎症和畸形的基本效应细胞。雷公藤红素是一种天然化合物，具有强大的抗关节炎作用，可促进由细胞内钙（Ca）动员介导的内质网（ER）应激。钙是调节多种细胞过程的第二信使。我们假设，影响胞质钙动员的化合物雷公藤红素可作为对抗类风湿性关节炎的新策略。为解决此问题，雷公藤红素被用作一种分子工具来检测由钙调节的炎症基因表达谱。我们证实，雷公藤红素处理可使患者来源的RASFs中的胞质钙动员。使用炎症和自身免疫PCR阵列并经独立定量PCR验证后发现，370个基因中有23个基因受钙动员调控。大多数已鉴定的基因被下调，并根据它们参与类风湿性关节炎发病机制的细胞反应分为五组。因此，基于文献综述生成了一个信号网络图，展示了连接这些基因产物功能的可能分子电路。此外，生物信息学分析表明，与三种美国食品药品监督管理局（FDA）批准的抗风湿药物（甲氨蝶呤、利妥昔单抗和托珠单抗）相比，雷公藤红素诱导的钙动员基因表达谱显示出一种新的作用模式。据我们所知，这是一项开创性工作，绘制了钙信号网络对类风湿性关节炎相关炎症基因表达的调控。
