@article{b8540d9675bd4195853dd4aeaa7336f3,
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-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.",
author = "Tony Muchamuel and Michael Basler and Aujay, {Monette A.} and Erika Suzuki and Kalim, {Khalid W.} and Christoph Lauer and Catherine Sylvain and Ring, {Eileen R.} and Jamie Shields and Jing Jiang and Peter Shwonek and Francesco Parlati and Demo, {Susan D.} and Bennett, {Mark K.} and Kirk, {Christopher J.} and Marcus Groettrup",
note = "Funding Information: We thank R. Deshaies for discussion and comments. We thank N. Shastri (University of California–Berkeley) for providing T cell hybridomas and V. Cerundulo (University of Oxford) for the contribution of recombinant vaccinia viruses. We acquired P14 (transgenic line 318) and RIP-GP mice from M. van den Broek, University Hospital Zurich. Psmb8−/− gene-targeted mice were obtained from J. Monaco, University of Cincinnati. We thank J. Mattar (Rheumatology, Ueberlingen-Nussdorf) for the collection of blood from individuals with rheumatoid arthritis and L. Klotz and P. Knolle for instructions on the TH17 differentiation assay. U. Beck is achnowledged for excellent technical assistance. This work was funded by the German National Science Foundation grant GR 1517/4-2 and the Swiss National Science Foundation grant 31003A_119699. K.W.K. holds a fellowship of the Graduate School Chemical Biology at University of Constance (KoRS-CB).",
year = "2009",
month = jul,
doi = "10.1038/nm.1978",
language = "English (US)",
volume = "15",
pages = "781--787",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "7",
}