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

T Muchamuel, M Basler, MA Aujay, E Suzuki… - Nature medicine, 2009 - nature.com
T Muchamuel, M Basler, MA Aujay, E Suzuki, KW Kalim, C Lauer, C Sylvain, ER Ring…
Nature medicine, 2009nature.com
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 …
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.
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