4-hydroxynonenal inhibits interleukin-1β converting enzyme

Lipid peroxidation results from the interaction of reactive oxygen species and polyunsaturated fatty acids. Metabolites generated from oxidative stress play an important role in the pathogenesis of a variety of diseases and biologic processes. One such product generated from lipid peroxidation is 4-hydroxynonenal (HNE). HNE is thiol reactive and exhibits numerous cellular effects. In this study, the inhibition of the cysteine protease, interleukin- 1β (IL-1β) converting enzyme (ICE), by HNE in human blood mononuclear cells was investigated. HNE blocked the release of lipopolysaccharide (LPS)- stimulated IL-1β (EC₅₀ 5 μM) and IL-10 (EC₅₀ 2 μM) in a dose-dependent manner and, to a lesser extent, tumor necrosis factor-α (TNF-α) (EC₅₀ 15 μM) release. However, LPS-stimulated elevation of intracellular proIL-1β levels was not affected by HNE treatment. HNE inhibited ICE activity in lysed cells in a similar dose-dependent manner, measured by hydrolysis of the fluorogenic substrate YVAD-AMC and recombinant proIL-1β. 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-dependent manner. Thus, low levels of HNE can suppress mononuclear cell release of IL-1β, probably by interacting with the active site cysteine of ICE. These results have implications for modulating mononuclear cell function during oxidative stress conditions.