Inhibition of Invariant Chain Processing, Antigen-Induced Proliferative Responses, and the Development of Collagen-Induced Arthritis and Experimental Autoimmune Encephalomyelitis by a Small Molecule Cysteine Protease Inhibitor
| العنوان: | Inhibition of Invariant Chain Processing, Antigen-Induced Proliferative Responses, and the Development of Collagen-Induced Arthritis and Experimental Autoimmune Encephalomyelitis by a Small Molecule Cysteine Protease Inhibitor |
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| المؤلفون: | Michael S. McQueney, Roy A. Johanson, Elizabeth A. Capper-Spudich, Josephine H. Fox, Patricia L. Podolin, John J. Peterson, Robert W. Marquis, Edit Kurali, T. Gregg Davis, Dennis S. Yamashita, Stephen M. LoCastro, Gerald J. Terfloth, Brian R. Smith, Donald C. Carpenter, Edward Long, Xiaoyang Dong, Brian Bolognese |
| المصدر: | The Journal of Immunology. 180:7989-8003 |
| بيانات النشر: | The American Association of Immunologists, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | Male, Encephalomyelitis, Autoimmune, Experimental, Pyridines, Encephalomyelitis, T cell, Immunology, Cysteine Proteinase Inhibitors, Lymphocyte Activation, Mice, Antigen, Leucine, Cell Line, Tumor, MHC class I, medicine, Splenocyte, Animals, Humans, Immunology and Allergy, Collagen Type II, Cells, Cultured, Benzofurans, Mice, Knockout, biology, Chemistry, Experimental autoimmune encephalomyelitis, Histocompatibility Antigens Class II, Azepines, medicine.disease, Arthritis, Experimental, Cathepsins, Molecular biology, Raji cell, Antigens, Differentiation, B-Lymphocyte, Mice, Inbred C57BL, medicine.anatomical_structure, Mice, Inbred DBA, Cell culture, biology.protein, Cattle, Female, Protein Processing, Post-Translational, Spleen |
| الوصف: | Members of the papain family of cysteine proteases (cathepsins) mediate late stage processing of MHC class II-bound invariant chain (Ii), enabling dissociation of Ii, and binding of antigenic peptide to class II molecules. Recognition of cell surface class II/Ag complexes by CD4+ T cells then leads to T cell activation. Herein, we demonstrate that a pan-active cathepsin inhibitor, SB-331750, attenuated the processing of whole cell Ii p10 to CLIP by Raji cells, and DBA/1, SJL/J, and C57BL/6 splenocytes. In Raji cells and C57BL/6 splenocytes, SB-331750 inhibited class II-associated Ii processing and reduced surface class II/CLIP expression, whereas in SB-331750-treated DBA/1 and SJL/J splenocytes, class II-associated Ii processing intermediates were undetectable. Incubation of lymph node cells/splenocytes from collagen-primed DBA/1 mice and myelin basic protein-primed SJL/J mice with Ag in the presence of SB-331750 resulted in concentration-dependent inhibition of Ag-induced proliferation. In vivo administration of SB-331750 to DBA/1, SJL/J, and C57BL/6 mice inhibited splenocyte processing of whole cell Ii p10 to CLIP. Prophylactic administration of SB-331750 to collagen-immunized/boosted DBA/1 mice delayed the onset and reduced the severity of collagen-induced arthritis (CIA), and reduced paw tissue levels of IL-1β and TNF-α. Similarly, treatment of myelin basic protein-primed SJL/J lymph node cells with SB-331750 delayed the onset and reduced the severity of adoptively transferred experimental autoimmune encephalomyelitis (EAE). Therapeutic administration of SB-331750 reduced the severity of mild/moderate CIA and EAE. These results indicate that pharmacological inhibition of cathepsins attenuates CIA and EAE, potentially via inhibition of Ii processing, and subsequent Ag-induced T cell activation. |
| تدمد: | 1550-6606 0022-1767 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::88df259ac244132f833d3d9196e414fd https://doi.org/10.4049/jimmunol.180.12.7989 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....88df259ac244132f833d3d9196e414fd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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