EFFECT OF PROTEASOME INHIBITORS ON MONOCYTIC I-KAPPA-B-ALPHA AND I-KAPPA-B-BETA DEPLETION, NF-KAPPA-B ACTIVATION, AND CYTOKINE PRODUCTION

We investigated the effect of proteasome inhibitors on the lipopolysac charide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-kappa B (NF-kappa B), Exposure of human monocytic THP-1 cells to ALLN and Mu87 3 prevented the LPS-induced degradation of I kappa B-alpha and -beta, as did the more potent proteasome inhibitor, PSI, whereas several calp ain inhibitors were ineffective, This was accompanied by the inhibitio n of nuclear NF-kappa B binding activity and NF-kappa B transcriptiona l activation, At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1 beta (IL-1 beta), wh ereas 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 inhibito rs. Furthermore, the production of TNF was efficiently suppressed by A LLN and PSI, less by Mu873, and not at all by calpain inhibitors. In p rimary human blood monocytes ALLN also prevented the LPS-induced degra dation of I kappa B-alpha and -beta, efficiently blocked the productio n of TNF and, to a lesser extent, IL-1 beta, whereas that of IL-8 was not inhibited, The expression of NF-kappa B-dependent monocytic cytoki nes may be selectively controlled by the proteasome, offering a potent ial therapeutic target in inflammatory disease.