GYF-21, an Epoxide 2-(2-Phenethyl)-Chromone Derivative, Suppresses Innate and Adaptive Immunity via Inhibiting STAT1/3 and NF-κB Signaling Pathways.

Ran Guo,Jun Li,Yue-Lin Song,Hui-Xia Huo,Zhi-Xiang Zhu,Peng-Fei Tu,Yu-Fan Gu,Shan-Shan Li,Yun-Fang Zhao

doi:10.3389/fphar.2017.00281

Ran Guo, Jun Li + Show 7 more

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https://doi.org/10.3389/fphar.2017.00281

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Abstract

Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system characterized by demyelinating plaques and axonal loss. Inhibition on over activation of innate and adaptive immunity provides a rationale strategy for treatment of multiple sclerosis. In the present study, we investigated the inhibitory effects of GYF-21, an epoxide 2-(2-phenethyl)-chromone derivative isolated from Chinese agarwood, on innate and adaptive immunity for revealing its potential to treat multiple sclerosis. The results showed that GYF-21 markedly inhibited the activation of microglia, and dendritic cells as well as neutrophils, all of which play important roles in innate immunity. Furthermore, GYF-21 significantly suppressed adaptive immunity via inhibiting the differentiation of naive CD4+ T cells into T helper 1 (Th1) and T helper 17 (Th17) cells, and suppressing the activation, proliferation, and IFN-γ secretion of CD8+ T cells. The mechanism study showed that GYF-21 evidently inhibited the activation of STAT1/3 and NF-κB signaling pathways in microglia. In conclusion, we demonstrated that GYF-21 can significantly inhibit innate and adaptive immunity via suppressing STAT1/3 and NF-κB signaling pathways, and has potential to be developed into therapeutic drug for multiple sclerosis.

Highlights

As an organ-specific autoimmune disease, multiple sclerosis (MS) is manifested by chronic inflammatory demyelination of the central nervous system (CNS) and is one of the foremost causes of non-traumatic neurological disability in young adults (Goverman, 2009; Dendrou et al, 2015)
T helper 1 (Th1) cells, characterized by the production of interferon-γ (IFN-γ), have been considered as the type of effector helper T cells that mediate the pathogenesis of MS; subsequently studies have indicated that interleukin 17 (IL-17)-producing T helper (Th17) cells are involved and play more important role in this pathogenesis than Th1 cells (Ogura et al, 2008; McGeachy et al, 2009; El-Behi et al, 2011; Lazarevic et al, 2011; 2-(2-Phenethyl)-Chromone Derivative with Immunosuppressive Activity
In order to investigate the immunosuppressive effects of GYF-21 under doses without cytotoxicity, the cytotoxicity of GYF-21 on microglia and splenocytes was evaluated with Cell Counting Kit-8 (CCK-8)

Summary

Introduction

As an organ-specific autoimmune disease, multiple sclerosis (MS) is manifested by chronic inflammatory demyelination of the central nervous system (CNS) and is one of the foremost causes of non-traumatic neurological disability in young adults (Goverman, 2009; Dendrou et al, 2015). Myeloid innate immune cells, such as microglia, dendritic cells, and neutrophils, are prominent constituents of inflammatory infiltrates in the CNS during MS. These cells serve as antigen presenting cells for the reactivation of infiltrating myelin-reactive CD4+ T cells and are thought to directly result in tissue damage through secretion of toxic factors (Wu and Laufer, 2007; Comabella et al, 2010; Starossom et al, 2012; Goldmann and Prinz, 2013; Jaillon et al, 2013; Nuyts et al, 2013; Steinbach et al, 2013; StrachanWhaley et al, 2014). The identification of immunosuppressive drugs with new mechanism and lesser adverse effects to treat MS is very urgently needed

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