期刊
NATURE MEDICINE
卷 15, 期 7, 页码 781-U12出版社
NATURE PORTFOLIO
DOI: 10.1038/nm.1978
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资金
- German National Science Foundation [GR 1517/4-2]
- Swiss National Science Foundation [31003A_ 119699]
- Graduate School Chemical Biology
- Swiss National Science Foundation (SNF) [31003A_119699] Funding Source: Swiss National Science Foundation (SNF)
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.
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