4-Hydroxynonenal inhibits interleukin-1 beta 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 in 4-hydroxynonenal (HNE). HNE is thiol reactive and exhibits 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 blocked the release of lipopolysaccharide (LPS)-stimulated IL-1 beta (EC50 5 microM) and IL-10 (EC50 2 microM) in a dose-dependent manner and, to a lesser extent, tumor necrosis factor-alpha (TNF-alpha) (EC50 15 microM) release. However, LPS-stimulated elevation of intracellular proIL-1 beta 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-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-dependent manner. Thus, low levels of HNE can suppress mononuclear cell release of IL-1 beta, probably by interacting with the active site cysteine of ICE. These results have implications for modulating mononuclear cell function during oxidative stress conditions.
Davis
D W
DW
Department of Internal Medicine, University of Texas Houston Health Science 77030, USA.
Hamilton
R F
RF
Holian
A
A
D000447:Aldehydes / Q000494:pharmacology*; D000704:Analysis of Variance; D020170:Caspase 1; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005456:Fluorescent Dyes; D006801:Humans; D006868:Hydrolysis; D007375:Interleukin-1 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D011994:Recombinant Proteins / Q000187:drug effects
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D005456:Fluorescent Dyes; D007375:Interleukin-1; D011994:Recombinant Proteins; D003546:Cysteine Endopeptidases; D020170:Caspase 1; C027576:4-hydroxy-2-nonenal