Section Molecular Immunology, Institute of Immunology, Heidelberg University, Heidelberg, Germany.
Division of Rheumatology, Department of Internal Medicine V, Heidelberg University, Heidelberg, Germany.
Front Immunol. 2018 Nov 14;9:2584. doi: 10.3389/fimmu.2018.02584. eCollection 2018.
The activity and function of T-cells are influenced by the intra- and extracellular redox milieu. Oxidative stress induces hypo responsiveness of untransformed T-cells. Vice versa increased glutathione (GSH) levels or decreased levels of reactive oxygen species (ROS) prime T-cell metabolism for inflammation, e.g., in rheumatoid arthritis. Therefore, balancing the T-cell redox milieu may represent a promising new option for therapeutic immune modulation. Here we show that sulforaphane (SFN), a compound derived from plants of the Brassicaceae family, e.g., broccoli, induces a pro-oxidative state in untransformed human T-cells of healthy donors or RA patients. This manifested as an increase of intracellular ROS and a marked decrease of GSH. Consistently, increased global cysteine sulfenylation was detected. Importantly, a major target for SFN-mediated protein oxidation was STAT3, a transcription factor involved in the regulation of T17-related genes. Accordingly, SFN significantly inhibited the activation of untransformed human T-cells derived from healthy donors or RA patients, and downregulated the expression of the transcription factor RORγt, and the T17-related cytokines IL-17A, IL-17F, and IL-22, which play a major role within the pathophysiology of many chronic inflammatory/autoimmune diseases. The inhibitory effects of SFN could be abolished by exogenously supplied GSH and by the GSH replenishing antioxidant N-acetylcysteine (NAC). Together, our study provides mechanistic insights into the mode of action of the natural substance SFN. It specifically exerts T17 prone immunosuppressive effects on untransformed human T-cells by decreasing GSH and accumulation of ROS. Thus, SFN may offer novel clinical options for the treatment of T17 related chronic inflammatory/autoimmune diseases such as rheumatoid arthritis.
T 细胞的活性和功能受到细胞内外氧化还原环境的影响。氧化应激会导致未转化的 T 细胞反应迟钝。相反，增加谷胱甘肽 (GSH) 水平或减少活性氧 (ROS) 水平会为 T 细胞的炎症代谢做好准备，例如在类风湿关节炎中。因此，平衡 T 细胞的氧化还原环境可能代表一种有前途的新的免疫调节治疗选择。在这里，我们表明，从十字花科植物，如西兰花中提取的化合物萝卜硫素 (SFN)，可诱导健康供体或 RA 患者的未转化人 T 细胞产生促氧化状态。这表现为细胞内 ROS 增加和 GSH 明显减少。一致地，检测到增加的全局半胱氨酸亚磺酰化。重要的是，SFN 介导的蛋白质氧化的主要靶标是 STAT3，一种参与调节 T17 相关基因的转录因子。因此，SFN 可显著抑制来自健康供体或 RA 患者的未转化人 T 细胞的激活，并下调转录因子 RORγt 和 T17 相关细胞因子 IL-17A、IL-17F 和 IL-22 的表达，这些细胞因子在许多慢性炎症/自身免疫性疾病的病理生理学中起主要作用。SFN 的抑制作用可以通过外源性提供的 GSH 和 GSH 补充抗氧化剂 N-乙酰半胱氨酸 (NAC) 来消除。总之，我们的研究提供了对天然物质 SFN 作用机制的深入了解。它通过降低 GSH 和 ROS 的积累，特异性地对未转化的人 T 细胞发挥 T17 倾向的免疫抑制作用。因此，SFN 可能为治疗 T17 相关的慢性炎症/自身免疫性疾病，如类风湿关节炎，提供新的临床选择。
