title: A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis.
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.
authors.affiliation: Proteolix, Inc., South San Francisco, California, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Muchamuel
authors.forename: Michael
authors.initials: M
authors.lastname: Basler
authors.forename: Monette A
authors.initials: MA
authors.lastname: Aujay
authors.forename: Erika
authors.initials: E
authors.lastname: Suzuki
authors.forename: Khalid W
authors.initials: KW
authors.lastname: Kalim
authors.forename: Christoph
authors.initials: C
authors.lastname: Lauer
authors.forename: Catherine
authors.initials: C
authors.lastname: Sylvain
authors.forename: Eileen R
authors.initials: ER
authors.lastname: Ring
authors.forename: Jamie
authors.initials: J
authors.lastname: Shields
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.forename: Peter
authors.initials: P
authors.lastname: Shwonek
authors.forename: Francesco
authors.initials: F
authors.lastname: Parlati
authors.forename: Susan D
authors.initials: SD
authors.lastname: Demo
authors.forename: Mark K
authors.initials: MK
authors.lastname: Bennett
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kirk
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
mesh_terms: 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
chemical_list: D016207:Cytokines; D009097:Multienzyme Complexes; D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex