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The proteasome inhibitor bortezomib inhibits T cell-dependent inflammatory responses

2010; Oxford University Press; Volume: 88; Issue: 1 Linguagem: Inglês

10.1189/jlb.1009666

1938-3673

Koichi Yanaba, Ayumi Yoshizaki, Eiji Muroi, Toshihide Hara, Fumihide Ogawa, Kazuhiro Shimizu, Shinichi Sato,

Peptidase Inhibition and Analysis

Abstract Bortezomib enhances T cell apoptosis by inhibiting NF-κB activation, thereby suppressing cutaneous T cell-dependent inflammatory responses by reducing interferon-γ production. CHS is a cutaneous, T cell-dependent, inflammatory reaction mediated mainly by antigen-specific effector T cells. Bortezomib is a proteasome inhibitor that has shown impressive efficacy for the treatment of multiple myeloma. In the current study, we have assessed the effect of bortezomib treatment of CHS in mice and found that bortezomib potently inhibited CHS responses. The attenuation of CHS responses was associated with decreased inflammatory cell infiltration in the challenged skin. Specifically, bortezomib-treated mice showed significantly decreased numbers of CD4+ and CD8+ T cells in the challenged skin and draining lymph nodes. Cytoplasmic IFN-γ production by CD4+ and CD8+ T cells in the draining lymph nodes was decreased substantially by bortezomib treatment. Notably, bortezomib enhanced T cell apoptosis by inhibiting NF-κB activation during CHS responses. Thus, bortezomib treatment is likely to induce T cell death, thereby suppressing CHS responses by reducing IFN-γ production. These findings suggest that bortezomib treatment could be a promising strategy for treating autoimmune and inflammatory disease.