A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental 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-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.
Muchamuel
Tony
T
Proteolix, Inc., South San Francisco, California, USA.
Basler
Michael
M
Aujay
Monette A
MA
Suzuki
Erika
E
Kalim
Khalid W
KW
Lauer
Christoph
C
Sylvain
Catherine
C
Ring
Eileen R
ER
Shields
Jamie
J
Jiang
Jing
J
Shwonek
Peter
P
Parlati
Francesco
F
Demo
Susan D
SD
Bennett
Mark K
MK
Kirk
Christopher J
CJ
Groettrup
Marcus
M
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D001169:Arthritis, Experimental / Q000188:drug therapy*; D016207:Cytokines / Q000096:biosynthesis*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors
D016207:Cytokines; D009097:Multienzyme Complexes; D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex