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-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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Authors | 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 |
Journal | Nature medicine
(Nat Med)
Vol. 15
Issue 7
Pg. 781-7
(Jul 2009)
ISSN: 1546-170X [Electronic] United States |
PMID | 19525961
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cytokines
- Multienzyme Complexes
- Oligopeptides
- PR-957
- Proteasome Inhibitors
- LMP7 protein
- Proteasome Endopeptidase Complex
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Topics |
- 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, physiology)
- Oligopeptides
(pharmacology, therapeutic use)
- Proteasome Endopeptidase Complex
- Proteasome Inhibitors
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