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(Journal of Leukocyte Biology. 2000;68:131-136.)
© 2000 by Society for Leukocyte Biology

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

Department of Microbiology and Immunology, Wake Forest University Medical Center, Winston-Salem, North Carolina

Correspondence: Steven Mizel, Dept. of Microbiology and Immunology, Wake Forest University Medical Center, Winston-Salem, NC 27157. E-mail: smizel{at}wfubmc.edu

Interleukin-1ß is a secreted protein that accumulates in the cytosol as an inactive precursor (pIL-1ß) before processing and release of biologically active protein. To understand the impact of this property on IL-1ß production, we examined the intracellular stability of pIL-1ß in lipopolysaccharide (LPS)-stimulated human monocytes. Precursor IL-1ß was degraded with a relatively short half-life of 2.5 h in the promonocytic cell line, THP-1, and in primary monocytes. MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal) stabilized pIL-1ß levels in THP-1 cells, suggesting that degradation was proteasome-mediated, but this inhibitor was toxic for primary monocytes, causing release of pIL-1ß as well as the cytoplasmic enzyme, lactate dehydrogenase (LDH) into supernatants. In contrast, clasto-lactacystin ß-lactone, a specific inhibitor of the proteasome, caused a dose-dependent stabilization of intracellular pIL-1ß, and this led to a corresponding increase in mIL-1ß and pIL-1ß but not LDH release into culture supernatants. Therefore, by regulating intracellular levels of precursor IL-1ß, the proteasome plays an important and previously unrecognized role in controlling the amount of biologically active IL-1ß that is exported by activated monocytes.

Key Words: THP-1 • MG132 • lactacystin • precursor interleukin-1ß • degradation

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