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.
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Authors | Yang Tan, Xingxin Wu, Jing Sun, Wenjie Guo, Fangyuan Gong, Fenli Shao, Tao Tan, Yi Cao, Bingfeng Zheng, Yanhong Gu, Yang Sun, Qiang Xu |
Journal | Biochemical pharmacology
(Biochem Pharmacol)
Vol. 123
Pg. 63-72
(Jan 01 2017)
ISSN: 1873-2968 [Electronic] England |
PMID | 27751819
(Publication Type: Journal Article)
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Copyright | Copyright © 2016 Elsevier Inc. All rights reserved. |
Chemical References |
- Ergot Alkaloids
- Indole Alkaloids
- Receptors, Interferon
- STAT1 Transcription Factor
- Stat1 protein, mouse
- fumigaclavine C
- interferon gamma receptor
- Interferon-gamma
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Topics |
- Animals
- Cell Differentiation
- Colitis
(immunology, prevention & control)
- Ergot Alkaloids
(pharmacology)
- Indole Alkaloids
(pharmacology)
- Interferon-gamma
(metabolism)
- Mice
- Mice, Inbred C57BL
- Receptors, Interferon
(metabolism)
- STAT1 Transcription Factor
(metabolism)
- Signal Transduction
- Th1 Cells
(cytology, immunology)
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