期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1998
卷号：95
期号：26
页码：15671-15676
DOI：10.1073/pnas.95.26.15671
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The transcription factor NF-{kappa}B activates a number of genes whose protein products are proinflammatory. In quiescent cells, NF-{kappa}B exists in a latent form and is activated via a signal-dependent proteolytic mechanism in which the inhibitory protein I{kappa}B is degraded by the ubiquitin-proteasome pathway. Consequently, inhibition of the proteasome suppresses activation of NF-{kappa}B. This suppression should therefore decrease transcription of many genes encoding proinflammatory proteins and should ultimately have an anti-inflammatory effect. To this end, a series of peptide boronic acid inhibitors of the proteasome, exemplified herein by PS-341, were developed. The proteasome is the large multimeric protease that catalyzes the final proteolytic step of the ubiquitin-proteasome pathway. PS-341, a potent, competitive inhibitor of the proteasome, readily entered cells and inhibited the activation of NF-{kappa}B and the subsequent transcription of genes that are regulated by NF-{kappa}B. Significantly, PS-341 displayed similar effects in vivo. Oral administration of PS-341 had anti-inflammatory effects in a model of Streptococcal cell wall-induced polyarthritis and liver inflammation in rats. The attenuation of inflammation in this model was associated with an inhibition of I{kappa}B degradation and NF-{kappa}B-dependent gene expression. These experiments clearly demonstrate that the ubiquitin-proteasome pathway and NF-{kappa}B play important roles in regulating chronic inflammation and that, as predicted, proteasome inhibition has an anti-inflammatory effect.
