A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis
A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis
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DOI：
10.1038/nm.1978
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发表时间：
2009-07-01
期刊：
影响因子：
82.9
通讯作者：
Groettrup, Marcus
中科院分区：
文献类型：
--
作者：
Muchamuel, Tony;Basler, Michael;Groettrup, Marcus
免疫蛋白酶体是一类主要存在于单核细胞和淋巴细胞中的蛋白酶体，已知其可形成I类主要组织相容性复合物（MHC-I）上呈递的抗原库。然而，免疫蛋白酶体在调节免疫反应的其他方面的具体作用尚未确定。我们在这里描述PR-957的特性，PR-957是低分子量多肽-7（LMP 7，由Psmb 8编码）的选择性抑制剂，免疫蛋白酶体的胰凝乳蛋白酶样亚基。PR-957在体外和体内阻断LMP 7特异性MHC-I限制性抗原的呈递。通过PR-957选择性抑制LMP 7阻断了活化的单核细胞产生白细胞介素-23（IL-23）以及T细胞产生干扰素-γ和IL-2。在类风湿性关节炎的小鼠模型中，PR-957治疗逆转了疾病的体征，并导致细胞浸润、细胞因子产生和自身抗体水平的降低。这些研究揭示了LMP 7在控制致病性免疫应答中的独特作用，并为靶向LMP 7治疗自身免疫性疾病提供了理论依据。
The immunoproteasome, a distinct class of proteasome found predominantly in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on class I major histocompatibility complexes (MHC-I). However, a specific role for the immunoproteasome in regulating other facets of immune responses has not been established. We describe here the characterization of PR-957, a selective inhibitor of low-molecular mass polypeptide-7 (LMP7, encoded by Psmb8), the chymotrypsin-like subunit of the immunoproteasome. PR-957 blocked presentation of LMP7-specific, MHC-I-restricted antigens in vitro and in vivo. Selective inhibition of LMP7 by PR-957 blocked production of interleukin-23 (IL-23) by activated monocytes and interferon-gamma and IL-2 by T cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and resulted in reductions in cellular infiltration, cytokine production and autoantibody levels. These studies reveal a unique role for LMP7 in controlling pathogenic immune responses and provide a therapeutic rationale for targeting LMP7 in autoimmune disorders.