BCL6 inhibitor FX1 attenuates inflammatory responses in murine sepsis through strengthening BCL6 binding affinity to downstream target gene promoters
BCL6 inhibitor FX1 attenuates inflammatory responses in murine sepsis through strengthening BCL6 binding affinity to downstream target gene promoters
复制标题
BCL6 抑制剂 FX1 通过增强 BCL6 与下游靶基因启动子的结合亲和力来减弱小鼠脓毒症的炎症反应
DOI：
10.1016/j.intimp.2019.105789
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发表时间：
2019-10-01
影响因子：
5.6
通讯作者：
Xia, Jiahong
中科院分区：
文献类型：
--
作者：
Zhang, Hao;Qi, Xiaoyui;Xia, Jiahong
背景资料。当感染触发错乱的炎症反应时，就会发生脓毒症。对于这种情况，没有有效的治疗方法。转录抑制因子B细胞淋巴瘤6(BCL6)被认为是巨噬细胞介导的炎症反应的抑制因子。FX1是一种新型的特异性BCL6 BTB抑制剂，能够减弱B细胞样弥漫性大B细胞淋巴瘤(ABC-DLBCL)的活性。然而，FX1在炎症反应和脓毒症中的作用尚不清楚。目的：探讨FX1对脂多糖诱导的脓毒症小鼠炎症反应的调节作用及其可能的机制。用ELISA法评估FX1对巨噬细胞和脓毒症模型小鼠血清中的促炎细胞因子的影响。采用流式细胞仪分析、Western印迹和qRT-PCR检测FX1治疗前后巨噬细胞免疫应答的变化。结果：FX1能显著提高脂多糖诱导的脓毒症小鼠的存活率。FX1可减少炎症细胞因子的产生，减轻巨噬细胞的侵袭活性，降低单核细胞的趋化活性，提示FX1具有抗炎作用。从机制上讲，FX1可增强BCL6与下游促炎症基因的亲和力。结论：FX1在脂多糖诱导的脓毒症中具有抗炎作用及其可能的机制。FX1可能成为脓毒症治疗中一种新的免疫抑制和抗炎药物候选药物。
Background. Sepsis occurs when an infection triggers deranged inflammatory responses. There exists no efficacious treatment for this condition. The transcriptional repressor B-cell Lymphoma 6 (BCL6) is known to act as an inhibitor of macrophage-mediated inflammatory responses. FX1, a novel specific BCL6 BTB inhibitor, is able to attenuate activity of B cell-like diffuse large B cell lymphoma (ABC-DLBCL). Nevertheless, the effect of FX1 in inflammatory responses and sepsis remains unknown.Objectives: Here, we explored the effect and potential mechanisms of FX1 on the regulation of LPS-induced inflammatory responses in murine sepsis.Method: Mice models of LPS-induced sepsis were monitored for survival rate following FX1 administration. ELISA was used to assess how FX1 administration affected pro-inflammatory cytokines present in macrophages exposed to LPS and in the serum of mice sepsis models. Flow cytometric analysis, Western blot and qRT-PCR were performed to evaluate differences in macrophages immune responses after FX1 pre-treatment. Finally, the affinity of BCL6 binding to downstream target genes was checked by ChIP.Results: The survival rate of mice models of LPS-induced sepsis was improved in following FX1 administration. FX1 decreased the production of inflammatory cytokines, attenuated macrophage infiltration activities and reduced monocytes chemotaxis activities, all of which suggest that FX1 exert anti-inflammatory effects. Mechanistically, FX1 may enhance the affinity of BCL6 binding to downstream target pro-inflammatory genes.Conclusions: These findings illustrated the anti-inflammatory properties and potential mechanisms of FX1 in sepsis caused by LPS. FX1 could potentially become a new immunosuppressive and anti-inflammatory drug candidate in sepsis therapy.