A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis

Nat Med. 2009 Jul;15(7):781-7. doi: 10.1038/nm.1978. Epub 2009 Jun 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / drug effects
  • Arthritis, Experimental / drug therapy*
  • Cytokines / biosynthesis*
  • Disease Progression
  • Female
  • Humans
  • Lymphocytic choriomeningitis virus / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / physiology
  • Oligopeptides / pharmacology*
  • Oligopeptides / therapeutic use
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors*


  • Cytokines
  • Multienzyme Complexes
  • Oligopeptides
  • PR-957
  • Proteasome Inhibitors
  • LMP7 protein
  • Proteasome Endopeptidase Complex