4-HYDROXYNONENAL INHIBITS INTERLEUKIN-1-BETA CONVERTING-ENZYME

Lipid peroxidation results from the interaction of reactive oxygen spe cies and polyunsaturated fatty acids. Metabolites generated from oxida tive stress play an important role in the pathogenesis of a variety of diseases and biologic processes. One such product generated from lipi d peroxidation is 4-hydroxynonenal (HNE). HNE is thiol reactive and ex hibits numerous cellular effects. In this study, the inhibition of the cysteine protease, interleukin-1 beta (IL-1 beta) converting enzyme ( ICE), by HNE in human blood mononuclear cells was investigated, HNE bl ocked the release of lipopolysaccharide (LPS)-stimulated IL-1 beta (EC 50 5 mu M) and IL-10 (EC50 2 mu M) in a dose-dependent manner and, to a lesser extent, tumor necrosis factor-alpha (TNF-alpha) (EC50 15 mu M ) release. However, LPS-stimulated elevation of intracellular proIL-1 beta levels was not affected by HNE treatment. HNE inhibited ICE activ ity in lysed cells in a similar dose-dependent manner, measured by hyd rolysis of the fluorogenic substrate YVAD-AMC and recombinant proIL-1 beta. To confirm that the inhibition of ICE activity by HNE was not an indirect effect, ICE activity was examined using purified recombinant human ICE (rHu-ICE). HNE inhibited rHu-ICE activity in a dose-depende nt manner. Thus, low levels of HNE can suppress mononuclear cell relea se of IL-1 beta, probably by interacting with the active site cysteine of ICE, These results have implications for modulating mononuclear ce ll function during oxidative stress conditions.