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

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

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BASLER, Michael, Elmer MAURITS, Gerjan DE BRUIN, Julia KOERNER, Herman S. OVERKLEEFT, Marcus GROETTRUP, 2018. Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome. In: British journal of pharmacology. 175(1), pp. 38-52. ISSN 0366-0826. eISSN 1476-5381. Available under: doi: 10.1111/bph.14069

@article{Basler2018-01Ameli-41103, title={Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome}, year={2018}, doi={10.1111/bph.14069}, 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 Koerner, Julia and Overkleeft, Herman S. and Groettrup, Marcus} }

2018-01 Basler, Michael de Bruin, Gerjan Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome Basler, Michael 2018-01-18T11:52:03Z Maurits, Elmer Groettrup, Marcus BACKGROUND AND PURPOSE<br />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.<br />EXPERIMENTAL APPROACH<br />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.<br />KEY RESULTS<br />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.<br />CONCLUSION AND IMPLICATIONS<br />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. eng Koerner, Julia Maurits, Elmer Overkleeft, Herman S. de Bruin, Gerjan Koerner, Julia Groettrup, Marcus Overkleeft, Herman S. 2018-01-18T11:52:03Z

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