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

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.