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Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome
- Source :
- British Journal of Pharmacology. 175:38-52
- Publication Year :
- 2017
- Publisher :
- Wiley, 2017.
-
Abstract
- 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 naive 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.
- Subjects :
- 0301 basic medicine
Pharmacology
Autoimmune disease
Chemistry
medicine.medical_treatment
Biological activity
medicine.disease_cause
medicine.disease
Autoimmunity
03 medical and health sciences
Haematopoiesis
030104 developmental biology
Cytokine
Proteasome
Immunology
Proteasome inhibitor
medicine
Cancer research
Cytokine secretion
medicine.drug
Subjects
Details
- ISSN :
- 00071188
- Volume :
- 175
- Database :
- OpenAIRE
- Journal :
- British Journal of Pharmacology
- Accession number :
- edsair.doi...........ec434ebaa26b790834de136ebab7d2cd