Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome
Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome
复制标题
选择性针对免疫蛋白酶体所有活性中心的抑制剂对自身免疫的改善作用
DOI：
10.1111/bph.14069
复制
发表时间：
2018-01-01
影响因子：
7.3
通讯作者：
Groettrup, Marcus
中科院分区：
文献类型：
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作者：
Basler, Michael;Maurits, Elmer;Groettrup, Marcus
背景与目的：多催化内肽酶复合体样-1 （β 2i）、低分子质量多肽（LMP） 2 （β 1i）和LMP7 （β 5i）是免疫蛋白酶体的蛋白水解活性亚基，免疫蛋白酶体是一种主要表达于造血细胞中的特殊类型的蛋白酶体。靶向LMP7已被证明在自身免疫性疾病的临床前模型中具有治疗效果。在这项研究中，我们研究了最近发现的一种免疫蛋白酶体抑制剂LU-005i的选择性和生物活性。实验方法采用荧光肽底物表征LU-005i和其他免疫蛋白酶体选择性抑制剂的特异性。在内毒素刺激的小鼠脾细胞和人外周血单核细胞（PBMCs）中，研究了蛋白酶体抑制对细胞因子释放的影响。在葡聚糖硫酸钠（DSS）诱导的结肠炎模型中，通过测量体重减轻和结肠长度来评估蛋白酶体抑制对炎症性肠病的影响。关键结果：slu -005i是首个针对所有三种蛋白水解活性免疫蛋白酶体亚基的人和小鼠免疫蛋白酶体选择性抑制剂。LU-005i可抑制内毒素刺激小鼠脾细胞或人脾细胞的细胞因子分泌。此外，在LU-005i的存在下，幼稚T辅助细胞向T辅助17细胞的分化受到损害。此外，LU-005i改善了dss诱导的结肠炎。结论和意义一种新型泛免疫蛋白酶体抑制剂的研究证实了该免疫蛋白酶体是治疗炎症性疾病的一个有希望的药物靶点，并且LMP7的单独抑制并不需要达到治疗效果。我们的研究结果将促进新一代具有最佳治疗效果的免疫蛋白酶体抑制剂的设计，用于临床治疗自身免疫和癌症。
BACKGROUND AND PURPOSEMulticatalytic endopeptidase complex-like-1 (beta 2i), low molecular mass polypeptide (LMP) 2 (beta 1i) and LMP7 (beta 5i) are the proteolytically active subunits of the immunoproteasome, a special type of proteasome mainly expressed in haematopoietic cells. Targeting LMP7 has been shown to be therapeutically effective in preclinical models of autoimmune diseases. In this study, we investigated the selectivity and biological activity of LU-005i, a recently described inhibitor of the immunoproteasome.EXPERIMENTAL APPROACHThe specificity of LU-005i and other immunoproteasome-selective inhibitors was characterized using fluorogenic peptide substrates. The effect of proteasome inhibition on cytokine release was investigated in endotoxin-stimulated mouse splenocytes or human peripheral blood mononuclear cells (PBMCs). The effect of proteasome inhibition on inflammatory bowel disease in the dextran sulfate sodium (DSS)-induced colitis model was assessed by measuring weight loss and colon length.KEY RESULTSLU-005i is the first human and mouse immunoproteasome-selective inhibitor that targets all three proteolytically active immunoproteasome subunits. LU-005i inhibited cytokine secretion from endotoxin-stimulated mouse splenocytes or human PBMCs. Furthermore, differentiation of naive T helper cells to T helper 17 cells was impaired in the presence of LU-005i. Additionally, LU-005i ameliorated DSS-induced colitis.CONCLUSION AND IMPLICATIONSThis study with a novel pan-immunoproteasome inhibitor substantiates that the immunoproteasome is a promising drug target for the treatment of inflammatory diseases and that exclusive inhibition of LMP7 is not necessary for therapeutic effectiveness. Our results will promote the design of new generations of immunoproteasome inhibitors with optimal therapeutic efficacy for clinical use in the treatment of autoimmunity and cancer.