Effect of proteasome inhibitors on monocytic IkB-a and -b depletion, NF-kB activation, and cytokine production

Abstract: We investigated the effect of protea-some inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription fac-tor, nuclear factor-kB (NF-kB). Exposure of hu-man monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of IkB-a and-b, as did the more potent proteasome inhibi-tor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-kB binding activity and NF-kB tran-scriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1b (IL-1b), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also pre-vented the LPS-induced degradation of IkB-a and-b, efficiently blocked the production of TNF and, to a lesser extent, IL-1b, whereas that of IL-8 was not inhibited. The expression of NF-kB-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease. J. Leukoc. Biol. 63