Proteasome-mediated regulation of interleukin-1 beta turnover and export in human monocytes

Interleukin-1 beta is a secreted protein that accumulates in the cytosol as an inactive precursor (pIL-1 beta) before processing and release of biolog ically active protein, To understand the impact of this property on IL-1 be ta production, we examined the intracellular stability of pIL-1 beta in lip opolysaccharide (LPS)-stimulated human monocytes. Precursor IL-1 beta was d egraded,vith a relatively short half-life of 2.5 h in the promonocytic cell line, TNP-1, and in primary monocytes. MG132 (carbobenzoxyl-leucinyl-leuci nyl-leucinal) stabilized pIL-1 beta levels in THP-1 cells, suggesting that degradation was proteasome-mediated, but this inhibitor was toxic for prima ry monocytes, causing release of pIL-1 beta as well as the cytoplasmic enzy me, lactate dehydrogenase (LDH) into supernatants, in contrast, clasto-lact acystin beta-lactone, a specific inhibitor of the proteasome, caused a dose -dependent stabilization of intracellular pIL-1 beta, and this led to a cor responding increase in mIL-1 beta and pIL-1 beta but not LDH release into c ulture supernatants, Therefore, by regulating intracellular levels of precu rsor IL-I beta, the proteasome plays an important and previously unrecogniz ed role in controlling; the amount of biologically active IL-1 beta that is exported by activated monocytes.