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EMBO Rep ; 19(12)2018 12.
Article in English | MEDLINE | ID: mdl-30279279

ABSTRACT

Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine-inducible proteasome variant comprising the proteolytic subunits LMP2 (ß1i), MECL-1 (ß2i), and LMP7 (ß5i). Targeting the immunoproteasome in pre-clinical models of autoimmune diseases with the epoxyketone inhibitor ONX 0914 has proven to be effective. ONX 0914 was previously described as a selective LMP7 inhibitor. Here, we show that PRN1126, developed as an exclusively LMP7-specific inhibitor, has limited effects on IL-6 secretion, experimental colitis, and experimental autoimmune encephalomyelitis (EAE). We demonstrate that prolonged exposure of cells with ONX 0914 leads to inhibition of both LMP7 and LMP2. Co-inhibition of LMP7 and LMP2 with PRN1126 and LMP2 inhibitors LU-001i or ML604440 impairs MHC class I cell surface expression, IL-6 secretion, and differentiation of naïve T helper cells to T helper 17 cells, and strongly ameliorates disease in experimental colitis and EAE. Hence, co-inhibition of LMP2 and LMP7 appears to be synergistic and advantageous for the treatment of autoimmune diseases.


Subject(s)
Autoimmunity , Proteasome Endopeptidase Complex/immunology , Proteasome Inhibitors/pharmacology , Protein Subunits/antagonists & inhibitors , Animals , Cell Differentiation , Cell Membrane Permeability , Colitis/immunology , Colitis/pathology , Cytokines/metabolism , Dextran Sulfate , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Epitopes/metabolism , Histocompatibility Antigens Class I/metabolism , Mice, Inbred C57BL , Proteasome Endopeptidase Complex/metabolism , Protein Subunits/immunology , Spleen/cytology , Th17 Cells/cytology , Th17 Cells/immunology
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