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

被引：6

作者：

Tan, Yang ^{[1
,2
]}

Wu, Xingxin ^{[1
,2
]}

Sun, Jing ^{[3
]}

Guo, Wenjie ^{[1
,2
]}

Gong, Fangyuan ^{[1
,2
]}

Shao, Fenli ^{[1
,2
]}

Tan, Tao ^{[1
,2
]}

Cao, Yi ^{[4
,5
]}

Zheng, Bingfeng ^{[1
,2
]}

Gu, Yanhong ^{[3
]}

Sun, Yang ^{[1
,2
]}

Xu, Qiang ^{[1
,2
]}

机构：

[1] Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Jiangsu, Peoples R China

[2] Nanjing Univ, Collaborat Innovat Ctr Chem Life Sci, Sch Life Sci, Nanjing 210023, Jiangsu, Peoples R China

[3] Nanjing Med Univ, Affiliated Hosp 1, Dept Oncol, Nanjing 210029, Jiangsu, Peoples R China

[4] Nanjing Univ, Natl Lab Solid State Microstruct, Nanjing 210023, Jiangsu, Peoples R China

[5] Nanjing Univ, Dept Phys, Nanjing 210023, Jiangsu, Peoples R China

来源：

BIOCHEMICAL PHARMACOLOGY | 2017年 / 123卷

基金：

中国国家自然科学基金;

关键词：

Colitis; T cell; T helper 1; IFN-gamma; FC9; INFLAMMATORY-BOWEL-DISEASE; T-BET; TRANSCRIPTION FACTOR; MURINE COLITIS; CROHNS-DISEASE; TGF-BETA; CELLS; IMMUNITY; TH1; INTERLEUKIN-12;

D O I：

10.1016/j.bcp.2016.10.004

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：63 / 72

页数：10

共 33 条

[1] MECHANISMS OF DISEASE Inflammatory Bowel Disease [J].