Roseotoxin B Improves Allergic Contact Dermatitis through a Unique Anti-Inflammatory Mechanism Involving Excessive Activation of Autophagy in Activated T Lymphocytes
Roseotoxin B Improves Allergic Contact Dermatitis through a Unique Anti-Inflammatory Mechanism Involving Excessive Activation of Autophagy in Activated T Lymphocytes
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玫瑰毒素 B 通过一种独特的抗炎机制改善过敏性接触性皮炎，该机制涉及激活 T 淋巴细胞中自噬的过度激活
DOI：
10.1016/j.jid.2016.04.017
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发表时间：
2016
影响因子：
6.5
通讯作者：
Xu Qiang
中科院分区：
文献类型：
--
作者：
Wang Xingqi;Hu Chunhui;Wu Xingxin;Wang Shiyu;Zhang Aihua;Chen Wei;Shen Yan;Tan Renxiang;Wu Xuefeng;Sun Yang;Xu Qiang
毒性可忽略或可接受的免疫抑制剂可能为治疗变应性接触性皮炎提供更好的治疗策略。我们鉴定了一种天然环肽，玫瑰毒素B，它能有效抑制活化T细胞中的细胞增殖和促炎细胞因子的产生，但在0.3-1 μmol/L的浓度下几乎没有幼稚T细胞毒性。此外，玫瑰毒素B抑制AKT和信号转导子与转录激活子-3的活化，抑制细胞周期相关信号，导致G 0/G1期阻滞，减少核糖体蛋白-S3（RPS 3）依赖的NF-κ B介导的IL-2产生，并增加活化T细胞的自噬。玫瑰毒素B能明显改善苦氯诱发的小鼠变应性接触性皮炎。玫瑰毒素B的作用在LC 3敲除小鼠中被抑制，表明玫瑰毒素B在T细胞介导的皮肤病中以自噬依赖性方式起作用。总的来说，这项研究显示了玫瑰毒素B诱导的自噬性细胞死亡的机制，并提供了一个独特的视角，自噬介导的NF-κB信号在活化的T细胞下调。玫瑰毒素B在变应性接触性皮炎中对活化T淋巴细胞的独特抗炎机制提示其可能成为治疗免疫相关性皮肤病的潜在靶点。
An immunosuppressant agent with negligible or acceptable toxicity may provide a better therapeutic strategy for treatment of allergic contact dermatitis. We identified a natural cyclopeptide, roseotoxin B, that effectively suppressed cell proliferation and the production of proinflammatory cytokines in activated T cells but exhibited little naive T-cell toxicity at concentrations of 0.3–1 μmol/L. In addition, roseotoxin B inhibited the activation of AKT and signal transducer and activator of transcription-3, suppressed cell cycle-related signaling, caused G0/G1phase arrest, reduced ribosomal protein-S3 (RPS3)–dependent NF-κB–mediated IL-2 production, and increased autophagy in activated T cells. Furthermore, picryl chloride-induced allergic contact dermatitis was significantly ameliorated by roseotoxin B in mice. The effects of roseotoxin B were inhibited in LC3-knockout mice, indicating that roseotoxin B acts in an autophagy-dependent manner in T-cell–mediated skin diseases. Overall, this study showed a mechanism for roseotoxin B-induced autophagic cell death and provided a unique perspective on autophagy-mediated down-regulation of NF-κB signaling in activated T cells. The unique anti-inflammatory mechanism of roseotoxin B against activated T lymphocytes in allergic contact dermatitis suggests that it could be a potential target for the treatment of immune-related skin diseases.