title: Regulation of constitutive neutrophil apoptosis by the alpha,beta-unsaturated aldehydes acrolein and 4-hydroxynonenal.
abstract: Reactive alpha,beta-unsaturated aldehydes are major components of common environmental pollutants and are products of lipid oxidation. Although these aldehydes have been demonstrated to induce apoptotic cell death in various cell types, we recently observed that the alpha,beta-unsaturated aldehyde acrolein (ACR) can inhibit constitutive apoptosis of polymorphonuclear neutrophils and thus potentially contribute to chronic inflammation. The present study was designed to investigate the biochemical mechanisms by which two representative alpha,beta-unsaturated aldehydes, ACR and 4-hydroxynonenal (HNE), regulate neutrophil apoptosis. Whereas low concentrations of either aldehyde (<10 microM) mildly promoted apoptosis in neutrophils (reflected by increased phosphatidylserine exposure, caspase-3 activation, and mitochondrial cytochrome c release), higher concentrations prevented critical features of apoptosis (caspase-3 activation, phosphatidylserine exposure) and caused delayed neutrophil cell death with characteristics of necrosis/oncosis. Inhibition of caspase-3 activation by either aldehyde occurred despite increases in mitochondrial cytochrome c release and occurred in close association with depletion of cellular GSH and with cysteine modifications within caspase-3. However, procaspase-3 processing was also prevented, because of inhibited activation of caspases-9 and -8 under similar conditions, suggesting that ACR (and to a lesser extent HNE) can inhibit both intrinsic (mitochondria dependent) and extrinsic mechanisms of neutrophil apoptosis at initial stages. Collectively, our results indicate that alpha,beta-unsaturated aldehydes can inhibit constitutive neutrophil apoptosis by common mechanisms, involving changes in cellular GSH status resulting in reduced activation of initiator caspases as well as inactivation of caspase-3 by modification of its critical cysteine residue.
authors.affiliation: Dept. of Pathology, College of Medicine, University of Vermont, 89 Beaumont Ave. Burlington, VT 05405, USA.
authors.forename: Erik I
authors.initials: EI
authors.lastname: Finkelstein
authors.forename: Jurjen
authors.initials: J
authors.lastname: Ruben
authors.forename: C Wendy
authors.initials: CW
authors.lastname: Koot
authors.forename: Milena
authors.initials: M
authors.lastname: Hristova
authors.forename: Albert
authors.initials: A
authors.lastname: van der Vliet
mesh_terms: D000171:Acrolein / Q000494:pharmacology*; D000393:Air Pollutants / Q000494:pharmacology*; D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000201:enzymology; D009336:Necrosis / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology*; D010718:Phosphatidylserines / Q000494:pharmacology
chemical_list: D000393:Air Pollutants; D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D010718:Phosphatidylserines; D000171:Acrolein; D045304:Cytochromes c; D020169:Caspases; D005978:Glutathione; C027576:4-hydroxy-2-nonenal