Selective proteasome inhibitors as anti-inflammatory agents

Abstract

Nuclear factor κB (NF-κB) is an ubiquitous transcription factor and pleiotropic regulator of numerous inflammatory and immune responses. Once activated, NF-κB translocates from the cytosol to the nucleus of the cell, where it binds to its consensus sequence on the promoter-enhancer region of different genes. By so doing, this activates the transcription of a variety of different pro-inflammatory cytokines, adhesion molecules and specific enzymes, such as the inducible forms of nitric oxide synthase and cyclooxygenase. A number of different cytokines, bacterial products and oxidants activate NF-κB via selective phosphorlyation, polyubiquitination and degradation of the inhibitor protein, IκB. Since the 26S proteasome complex degrades the post-translationally modified IκB, thereby liberating the transcriptionally active p50/p65 heterodimeric NF-κB, this proteolytic complex represents a critical step in the activation of NF-κB. This review discusses the basic biology of the ubiquitin-proteasome pathway as it relates to the inflammatory response, and highlights those studies demonstrating that selective proteasome inhibitors are effective anti-inflammatory agents in vivo.

• arthritis
• colitis
• gastropathy
• inflammation
• nuclear factor-κB
• nitric oxide
• non-steroidal anti-inflammatory drugs
• oxidants