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The epigenetic roles of BET inhibitors JQ1 and I-BET726 in regulating inflammation and treatment for experimental autoimmune encephalomyelitis

Li, Q;Zhang, D;Chen, R;Shi, L;Shi, Y;Gao, F;

The epigenetic factor bromodomain and extra-terminal domain (BET) proteins have multiple functions in regulating cell proliferation, differentiation and inflammation via binding to acetylated lysines on histones. JQ1 and I-BET726, new inhibitors of BET proteins, have potential therapeutic benefit for autoimmune diseases (AD). In this study, we explored the effects of JQ1 and I-BET726 on innate and adaptive immunity in experimental autoimmune encephalomyelitis (EAE) model to investigate the mechanism and therapeutic benefit for AD. The effects of JQ1 and I-BET726 on LPS-induced inflammation were investigated in innate and adaptive immune cells of dendritic cells (DCs), macrophages, and DC-dependent T cells. Different pro-inflammatory cytokines were assessed via real-time PCR, flow cytometry, and Elispot. Moreover, the effects of JQ1 and I-BET726 on EAE animals were further investigated, including the effects on alleviating clinical symptoms and inhibiting inflammation and demyelination in spinal cords via real-time PCR and immunohistochemical staining. JQ1 and I-BET726 efficiently inhibited LPS-increased TNF-α and IL-6 expression in bone marrow-derived DC and macrophage of Raw264.7 cells. They also suppressed adaptive immunity by down-regulating CD80/CD86 and IL-12/GM-CSF expressions, and inhibiting DC-dependent T cell priming. Moreover, they effectively inhibited TNF-α and IL-6 involved inflammatory changes in the spinal cords of EAE model, including inflammatory cell infiltration and demyelination. Most importantly, JQ1 and I-BET726 efficiently attenuated the clinical deterioration of EAE mice. Our results indicate that JQ1 and I-BET726 possess therapeutic benefits for autoimmune diseases by adjusting innate and adaptive immune response, indicating that BET bromodomain might be potential molecular targets for autoimmune disease therapy.