A fumigaclavine C isostere alleviates Th1-mediated experimental colitis via competing with IFN-γ for binding to IFN-γ receptor 1

详细信息    查看全文

• 作者：Yang Tan^a ; ¹ ; Xingxin Wu^a ; ¹ ; ^{xingxin.wu@nju.edu.cn} ; Jing Sun^b ; Wenjie Guo^a ; Fangyuan Gong^a ; Fenli Shao^a ; Tao Tan^a ; Yi Cao^c ; Bingfeng Zheng^a ; Yanhong Gu^b ; Yang Sun^a ; ^{yangsun@nju.edu.cn} ; Qiang Xu^a ; ^{molpharm@163.com}
• 关键词：Colitis ; T cell ; T helper 1 ; IFN-γ ; FC9
• 刊名：Biochemical Pharmacology
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：123
• 期：Complete
• 页码：63-72
• 全文大小：3324 K
• 卷排序：123

文摘

Interferon gamma (IFN-γ) signaling in T cells plays an important role in developing T helper 1 (Th1)-mediated inflammation. Selective regulation of IFN-γ signaling is an attractive strategy for treating Th1-mediated immune diseases. In this study, we aimed to explore possible means of targeting IFN-γ signaling by using small molecule compound. A synthetic small molecule FC9 was identified as it selectively inhibited IFN-γ signaling in T cells without suppressing interleukin 4 (IL-4) signaling. Furthermore, FC9 inhibited IFN-γ-induced Janus kinase 2 (JAK2) activation via competing with IFN-γ for binding to IFN-γ receptor 1 (IFN-γ R1). Interestingly, we found that FC9 bound to IFN-γ 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-γ R1 for selective inhibition of IFN-γ signaling, demonstrated a novel mean of targeting IFN-γ signaling. These findings could lead to increased options for the treatment of Crohn’s disease and other Th1-mediated inflammatory diseases.