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

Tony Muchamuel, Michael Basler, Monette A. Aujay, Erika Suzuki, Khalid W. Kalim, Christoph Lauer, Catherine Sylvain, Eileen R. Ring, Jamie Shields, Jing Jiang, Peter Shwonek, Francesco Parlati, Susan D. Demo, Mark K. Bennett, Christopher J. Kirk, Marcus Groettrup

Research output: Contribution to journalArticlepeer-review

469 Scopus citations

Abstract

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-γ 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.

Original languageEnglish (US)
Pages (from-to)781-787
Number of pages7
JournalNature medicine
Volume15
Issue number7
DOIs
StatePublished - Jul 2009
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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