Details

Autor(en) / Beteiligte

• Palombella, Vito J.
• Conner, Elaine M.
• Fuseler, John W.
• Destree, Antonia
• Davis, Jonathan M.
• Laroux, F. Stephen
• Wolf, Robert E.
• Huang, Jianqing
• Brand, Stephen
• Elliott, Peter J.
• Lazarus, Douglas
• McCormack, Teresa
• Parent, Lana
• Stein, Ross
• Adams, Julian
• Grisham, Matthew B.

Titel

Role of the Proteasome and NF-κ B in Streptococcal Cell Wall-Induced Polyarthritis

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 1998-12, Vol.95 (26), p.15671-15676

Ort / Verlag

National Academy of Sciences of the United States of America

Erscheinungsjahr

1998

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• The transcription factor NF-κ B activates a number of genes whose protein products are proinflammatory. In quiescent cells, NF-κ B exists in a latent form and is activated via a signal-dependent proteolytic mechanism in which the inhibitory protein Iκ B is degraded by the ubiquitin-proteasome pathway. Consequently, inhibition of the proteasome suppresses activation of NF-κ 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-κ B and the subsequent transcription of genes that are regulated by NF-κ 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 Iκ Bα degradation and NF-κ B-dependent gene expression. These experiments clearly demonstrate that the ubiquitin-proteasome pathway and NF-κ B play important roles in regulating chronic inflammation and that, as predicted, proteasome inhibition has an anti-inflammatory effect.