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Nature Medicine 15, 781 - 787 (2009)
Published online: 14 June 2009 | doi:10.1038/nm.1978



There is an Erratum (November 2009) associated with this Article.

A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis

Tony Muchamuel1,4, Michael Basler2,3,4, Monette A Aujay1, Erika Suzuki1, Khalid W Kalim3, Christoph Lauer3, Catherine Sylvain1, Eileen R Ring1, Jamie Shields1, Jing Jiang1, Peter Shwonek1, Francesco Parlati1, Susan D Demo1, Mark K Bennett1, Christopher J Kirk1 & Marcus Groettrup2,3

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.