Regulation of constitutive neutrophil apoptosis by the alpha,beta-unsaturated aldehydes acrolein and 4-hydroxynonenal.
Regulation of constitutive neutrophil apoptosis by the alpha,beta-unsaturated aldehydes acrolein and 4-hydroxynonenal.
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发表时间：
2005
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通讯作者：
E. Finkelstein;J. Ruben;C. Koot;Milena Hristova;A. van der Vliet
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作者：
E. Finkelstein;J. Ruben;C. Koot;Milena Hristova;A. van der Vliet
活性α、β-不饱和醛是常见环境污染物的主要成分，是脂质氧化的产物。虽然这些醛已经被证明在不同类型的细胞中诱导细胞凋亡，但我们最近观察到，α，β-不饱和醛丙烯醛(ACR)可以抑制中性粒细胞的结构性凋亡，从而可能导致慢性炎症。本研究旨在探讨两种具有代表性的α-β-不饱和醛--ACR和4-羟基壬烯醛(HNE)调节中性粒细胞凋亡的生化机制。虽然低浓度的醛(10微米)温和地促进中性粒细胞的凋亡(反映为磷脂酰丝氨酸暴露、caspase-3激活和线粒体细胞色素c释放)，但较高浓度阻止了凋亡的关键特征(caspase-3激活、磷脂酰丝氨酸暴露)，并导致中性粒细胞迟发性死亡，具有坏死/肿胀的特征。尽管线粒体细胞色素c的释放增加，但任一醛对caspase-3的激活仍有抑制作用，并且与细胞内GSH的耗竭和caspase-3内的半胱氨酸修饰密切相关。然而，由于在相似的条件下抑制了caspase-9和-8的激活，Proaspase-3的处理也被阻止，这表明ACR(以及较小程度的HNE)在最初阶段可以抑制中性粒细胞凋亡的内在(线粒体依赖)和外在机制。综上所述，我们的结果表明，α，β-不饱和醛可以通过共同的机制抑制构成性中性粒细胞的凋亡，包括改变细胞内GSH状态，导致启动子caspase的激活减少，以及通过修改其关键的半胱氨酸残基来使caspase-3失活。
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.