A fumigaclavine C isostere alleviates Th1-mediated experimental colitis via competing with IFN-γ for binding to IFN-γ receptor 1
A fumigaclavine C isostere alleviates Th1-mediated experimental colitis via competing with IFN-γ for binding to IFN-γ receptor 1
复制标题
烟加拉维 C 电子等排体通过与 IFN-γ 竞争与 IFN-γ 受体 1 的结合来缓解 Th1 介导的实验性结肠炎。
DOI：
10.1016/j.bcp.2016.10.004
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发表时间：
2017-01-01
影响因子：
5.8
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
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作者：
Tan, Yang;Wu, Xingxin;Xu, Qiang
T细胞中的干扰素γ（IFN-γ）信号传导在发展辅助性T细胞1（Th 1）介导的炎症中起重要作用。IFN-γ信号的选择性调节是治疗Th 1介导的免疫疾病的有吸引力的策略。在这项研究中，我们的目的是探索通过使用小分子化合物靶向IFN-γ信号转导的可能方法。合成的小分子FC 9被鉴定为选择性抑制T细胞中的IFN-γ信号传导而不抑制白细胞介素4（IL-4）信号传导。此外，FC 9通过与IFN-γ竞争结合IFN-γ受体1（IFN-γ R1）来抑制IFN-γ诱导的Janus激酶2（JAK 2）活化。有趣的是，我们发现FC 9与IFN-γ R1结合并选择性抑制T细胞中的Th 1而不是Th 2免疫应答，从而改善了2，4，6-三硝基苯磺酸（TNBS）诱导的小鼠结肠炎。总之，FC 9诱导的竞争性阻断IFN-γ R1以选择性抑制IFN-γ信号传导，证明了靶向IFN-γ信号传导的新方法。这些发现可能会增加克罗恩病和其他Th 1介导的炎症性疾病的治疗选择。(c)2016 Elsevier Inc. All rights reserved.
Interferon gamma (IFN-gamma) signaling in T cells plays an important role in developing T helper 1 (Th1)-mediated inflammation. Selective regulation of IFN-gamma signaling is an attractive strategy for treating Th1-mediated immune diseases. In this study, we aimed to explore possible means of targeting IFN-gamma signaling by using small molecule compound. A synthetic small molecule FC9 was identified as it selectively inhibited IFN-gamma signaling in T cells without suppressing interleukin 4 (IL-4) signaling. Furthermore, FC9 inhibited IFN-gamma-induced Janus kinase 2 (JAK2) activation via competing with IFN-gamma for binding to IFN-gamma receptor 1 (IFN-gamma R1). Interestingly, we found that FC9 bound to IFN-gamma R1 and selectively suppressed Th1 but not Th2 immune response in T cells, resulting in an improvement in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. In conclusion, FC9-induced competitive blockade of IFN-gamma R1 for selective inhibition of IFN-gamma signaling, demonstrated a novel mean of targeting IFN-gamma signaling. These findings could lead to increased options for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases. (c) 2016 Elsevier Inc. All rights reserved.