BJ-2266 ameliorates experimental autoimmune encephalomyelitis through down-regulation of the JAK/STAT signaling pathway

5 years ago

BJ-2266 ameliorates experimental autoimmune encephalomyelitis through down-regulation of the JAK/STAT signaling pathway

Byeong-Seon Jeong, Maheshwor Timilshina, Zhiwei You, Jae-Hoon Chang

CD4+ T cells differentiate into distinct effector subsets upon antigenic stimulation. Cytokines, and micro-environmental factors present during T-cell priming, direct differentiation of naïve CD4+ T cells into pro-inflammatory Th1 and Th17 cells. From extensive screening of 2,4,5-trimethylpyridin-3-ol derivatives with various functional groups at C(6)-position, BJ-2266, a 6-thioureido-derivative, showed potent inhibitory activity on in vitro T helper (Th)-cell differentiation. This compound inhibited IFN-γ and IL-17 production from polyclonal CD4+ T cells and ovalbumin (OVA)-specific CD4+ T cells that were activated by T-cell receptor (TCR) engagement. We assessed the inhibitory effect of BJ-2266 in experimental autoimmune encephalomyelitis (EAE). Our results suggest that BJ-2266 treatment significantly suppresses EAE disease progression with reduced generation of Th1 and Th17 cells. Notably, Th-cell differentiation was significantly suppressed by BJ-2266 treatment with no effect on apoptosis, activation and proliferation of activated T cells. Furthermore, adoptive transfer of BJ-2266 treated MOG-reactive Th1 and Th17 cells led to a lower EAE disease score and better clinical recovery from EAE. The underlying mechanism of BJ-2266 effect involved the inhibition of JAK/STAT phosphorylation that is critical for Th-cell differentiation. We conclude that BJ-2266 regulates the JAK/STAT pathway in response to cytokine signals and subsequently suppresses the differentiation of Th-cell responses. Proposed control of JAK/STAT signaling by BJ-2266: JAK/STAT signaling pathway has major roles in IL-12 induced Th1 as well as IL-6 and TGF-β induced Th17 differentiation and function. Inhibition of JAK/STAT by BJ-2266 contributed to a significant decrease in Th1/Th17 differentiation and hence reduced the EAE disease severity.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/eji.201646860