Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome

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2018
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Maurits, Elmer
de Bruin, Gerjan
Overkleeft, Herman S.
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British journal of pharmacology. 2018, 175(1), pp. 38-52. ISSN 0366-0826. eISSN 1476-5381. Available under: doi: 10.1111/bph.14069
Zusammenfassung

BACKGROUND AND PURPOSE
Multicatalytic endopeptidase complex-like-1 (β2i), low molecular mass polypeptide (LMP) 2 (β1i) and LMP7 (β5i) are the proteolytically active subunits of the immunoproteasome, a special type of proteasome mainly expressed in haematopoietic cells. Targeting LMP7 has been shown to be therapeutically effective in preclinical models of autoimmune diseases. In this study, we investigated the selectivity and biological activity of LU-005i, a recently described inhibitor of the immunoproteasome.
EXPERIMENTAL APPROACH
The specificity of LU-005i and other immunoproteasome-selective inhibitors was characterized using fluorogenic peptide substrates. The effect of proteasome inhibition on cytokine release was investigated in endotoxin-stimulated mouse splenocytes or human peripheral blood mononuclear cells (PBMCs). The effect of proteasome inhibition on inflammatory bowel disease in the dextran sulfate sodium (DSS)-induced colitis model was assessed by measuring weight loss and colon length.
KEY RESULTS
LU-005i is the first human and mouse immunoproteasome-selective inhibitor that targets all three proteolytically active immunoproteasome subunits. LU-005i inhibited cytokine secretion from endotoxin-stimulated mouse splenocytes or human PBMCs. Furthermore, differentiation of naïve T helper cells to T helper 17 cells was impaired in the presence of LU-005i. Additionally, LU-005i ameliorated DSS-induced colitis.
CONCLUSION AND IMPLICATIONS
This study with a novel pan-immunoproteasome inhibitor substantiates that the immunoproteasome is a promising drug target for the treatment of inflammatory diseases and that exclusive inhibition of LMP7 is not necessary for therapeutic effectiveness. Our results will promote the design of new generations of immunoproteasome inhibitors with optimal therapeutic efficacy for clinical use in the treatment of autoimmunity and cancer.

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570 Biowissenschaften, Biologie
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ISO 690BASLER, Michael, Elmer MAURITS, Gerjan DE BRUIN, Julia KÖRNER, Herman S. OVERKLEEFT, Marcus GRÖTTRUP, 2018. Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome. In: British journal of pharmacology. 2018, 175(1), pp. 38-52. ISSN 0366-0826. eISSN 1476-5381. Available under: doi: 10.1111/bph.14069
BibTex
@article{Basler2018-01Ameli-41103,
  year={2018},
  doi={10.1111/bph.14069},
  title={Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome},
  number={1},
  volume={175},
  issn={0366-0826},
  journal={British journal of pharmacology},
  pages={38--52},
  author={Basler, Michael and Maurits, Elmer and de Bruin, Gerjan and Körner, Julia and Overkleeft, Herman S. and Gröttrup, Marcus}
}
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