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A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis
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A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis
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Journal Article
A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis
2009
Overview
Christopher Kirk and his colleagues have developed the first specific inhibitor of the immunoproteasome. They find that the immunoproteasome has a major role in regulating cytokine production, as well as antigen presentation, and their inhibitor has good efficacy in animal models of arthritis.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Antigen Presentation - drug effects
/ Antigens
/ Arthritis, Experimental - drug therapy
/ Biomedical and Life Sciences
/ Female
/ Humans
/ Lymphocytic choriomeningitis virus - immunology
/ Major histocompatibility complex
/ Male
/ Mice
/ Multienzyme Complexes - antagonists & inhibitors
/ Multienzyme Complexes - physiology
/ Oligopeptides - pharmacology
/ Oligopeptides - therapeutic use
/ Proteasome Endopeptidase Complex
/ Rodents
