title: A fumigaclavine C isostere alleviates Th1-mediated experimental colitis via competing with IFN-γ for binding to IFN-γ receptor 1.
abstract: 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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China. Electronic address: xingxin.wu@nju.edu.cn.
authors.forename: Xingxin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Gong
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Fenli
authors.initials: F
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Tan
authors.affiliation: National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing 210023, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
authors.forename: Bingfeng
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China. Electronic address: yangsun@nju.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China. Electronic address: molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003092:Colitis / Q000276:immunology / Q000517:prevention & control*; D004876:Ergot Alkaloids / Q000494:pharmacology*; D026121:Indole Alkaloids / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017471:Receptors, Interferon / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D000096743:Interferon gamma Receptor
chemical_list: D004876:Ergot Alkaloids; D026121:Indole Alkaloids; D007371:Interferon-gamma; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse; C492995:fumigaclavine C
keywords: Colitis; FC9; IFN-γ; T cell; T helper 1