Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity
| Autor: | Claire L Langrish, Marcus Groettrup, Christian Schmidt, Michelle M Lindstrom, Timothy D. Owens, Christopher J. Kirk, J. Michael Bradshaw, Michael Basler, Jacob LaStant, Elmer Maurits, Christopher Tsu, Herman S. Overkleeft |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Cell Membrane Permeability Encephalomyelitis Autoimmune Experimental Cell Autoimmunity medicine.disease_cause Biochemistry 03 medical and health sciences Epitopes 0302 clinical medicine ddc:570 MHC class I Genetics medicine Animals Secretion Molecular Biology Autoimmune disease biology Chemistry Experimental autoimmune encephalomyelitis Dextran Sulfate Histocompatibility Antigens Class I Cell Differentiation Articles medicine.disease Colitis autoimmune disease immunoproteasome immunoproteasome inhibitor design proteasome Mice Inbred C57BL Haematopoiesis Protein Subunits 030104 developmental biology medicine.anatomical_structure Proteasome biology.protein Cancer research Cytokines Th17 Cells Proteasome Inhibitors Spleen 030215 immunology |
| Zdroj: | EMBO reports. 19(12) |
| ISSN: | 1469-3178 |
| Popis: | Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine-inducible proteasome variant comprising the proteolytic subunits LMP2 (β1i), MECL-1 (β2i), and LMP7 (β5i). 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. published |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text