摘要
生发中心(germinal center,GC)的形成和自身抗体的产生常见于多种自身免疫性疾病。在GC形成过程中,滤泡辅助性T细胞(T follicular helper cell,Tfh cell)和生发中心B细胞(germinal center B cell,GC B cell)是不可或缺的。B细胞淋巴瘤6(B cell lymphoma 6,BCL6)是Tfh细胞和GC B细胞的重要转录因子,这两种细胞类型中BCL6的缺失会导致GC反应的终止。本文以BCL6为靶点,以均相时间分辨荧光(homogeneous timeresolved fluorescence,HTRF)为筛选方法,发现了靶向BCL6BTB结构域的新型高效小分子抑制剂WK429。在体外,WK429抑制外周血单个核细胞(peripheral blood mononuclear cell,PBMC)和Raw264.7细胞产生炎症因子IL-6和TNF-α,抑制Raw264.7细胞表达趋化因子CCL2和CCL7,也抑制Tfh细胞和GC B细胞的形成及浆细胞的形成和分裂;在体内,WK429同样抑制Tfh细胞、GC B细胞和浆细胞的形成,同时明显降低抗体IgG的产生。本研究显示,WK429能抑制炎症和降低体液免疫反应,这为体液免疫反应过强的自身免疫性疾病的预防或治疗提供了新的策略。
The germinal center(GC)formation and autoantibody production are found in various autoimmune diseases.T follicular helper(Tfh)cells and germinal center B(GC B)cells are indispensable during GC formation.B cell lymphoma 6(BCL6)is a main transcription factor of Tfh cells and GC B cells.Loss of BCL6 in these two cell types results in abrogation of the GC reaction.Herein,small molecule compound WK429 targeting BCL6BTB domain was discovered by homogeneous time-resolved fluorescence(HTRF)screening system.In vitro,WK429 inhibited the production of inflammatory factors IL-6 and TNF-αin peripheral blood mononuclear cells(PBMCs)and Raw264.7 cells,and also diminished the mRNA abundance of chemokine genes(CCL2 and CCL7)in Raw264.7 cells.WK429 not only restrained the formation of Tfh cells,GC B cells and plasma cells,but also depressed the division of plasma cells.In vivo,WK429 similarly restrained the formation of Tfh cells,GC B cells and plasma cells,and dramatically decreased the production of IgG antibodies.Collectively,this study demonstrated that WK429 could inhibit inflammation and reduce humoral immune responses,which may provide new strategies for the prevention or treatment of autoimmune diseases with excessive humoral immune responses.
作者
胡盼
邢雅婧
彭世鸿
谢玖清
郭伟凯
谢佳伊
刘明耀
易正芳
HU Pan;XING Ya-jing;PENG Shi-hong;XIE Jiu-qing;GUO Wei-kai;XIE Jia-yi;LIU Ming-yao;YI Zheng-fang(Shanghai Key Laboratory of Regulatory Biology,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai 200241,China)
出处
《生命科学研究》
CAS
CSCD
2020年第5期382-395,共14页
Life Science Research
基金
国家自然科学基金面上项目(81773204)。
