Trichomide A, a Natural Cyclodepsipeptide, Exerts Immunosuppressive Activity against Activated T Lymphocytes by Upregulating SHP2 Activation to Overcome Contact Dermatitis
Trichomide A, a Natural Cyclodepsipeptide, Exerts Immunosuppressive Activity against Activated T Lymphocytes by Upregulating SHP2 Activation to Overcome Contact Dermatitis
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Trichomide A 是一种天然环缩肽，通过上调 SHP2 激活对激活的 T 淋巴细胞发挥免疫抑制活性，从而克服接触性皮炎
DOI：
10.1038/jid.2014.252
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发表时间：
2014
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;Zhang Aihua;Gao Jian;Chen Wei;Wang Shiyu;Wu Xuefeng;Shen Yan;Ke Yuehai;Hua Zichun;Tan Renxiang;Sun Yang;Xu Qiang
越来越多的人患有过敏性接触性皮炎。然而，具有可忽略的毒性的免疫抑制剂候选物仍然是缺乏的。在本研究中，我们鉴定了一种名为毛滴虫A的天然环缩酚肽，其在0.3-3 μM时有效抑制活化T细胞的增殖并减少促炎细胞因子的产生，但对初始T细胞几乎没有毒性作用。此外，毛滴虫A还可诱导活化T细胞发生G 0/G1期阻滞，抑制AKT和STAT 3的活化，并以剂量和时间依赖性方式增加磷酸化SHP 2的水平。此外，在体内实验表明，滴虫A显着改善苦氯（PCI）诱导的小鼠接触过敏。通过在T细胞中使用SHP 2特异性抑制剂PHPS 1或条件性SHP 2敲除小鼠抑制SHP 2活性，上述实验中的毛滴虫A的这种作用被显著逆转，表明毛滴虫A的SHP 2依赖性作用。总之，毛滴虫A在体外和体内均表现出对T细胞介导的免疫应答的免疫抑制活性，这对于治疗免疫相关的皮肤病具有潜力。
Increasing numbers of people are suffering from allergic contact dermatitis. However, the immunosuppressive drug candidate with negligible toxicity is still deficient. In the present study, we identified a natural cyclodepsipeptide named trichomide A that effectively inhibited the proliferation of activated T cells and reduced the production of proinflammatory cytokines but had almost no toxic effect on naive T cells at 0.3–3 μM. In addition, trichomide A caused G0/G1 phase arrest, suppressed the activation of AKT and STAT3, and increased the level of phosphorylated SHP2 in activated T cells in dose- and time-dependent manners. Furthermore, anin vivoexperiment demonstrated that trichomide A significantly ameliorated picryl chloride (PCI)–induced contact hypersensitivity in mice. Such effects of trichomide A in the aforementioned experiments were significantly reversed by the inhibition of SHP2 activity using the SHP2-specific inhibitor PHPS1 or conditional SHP2 knockout mice in T cells, suggesting the SHP2-dependent action of trichomide A. Taken together, trichomide A showed an immunosuppressive activity against T cell–mediated immune responses bothin vitroandin vivo, which has potential for the treatment of immune-related skin diseases.