Thomas C E, Jackson R L, Ohlweiler D F, Ku G
Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
J Lipid Res. 1994 Mar;35(3):417-27.
Oxidized low density lipoproteins (LDL) induce the release of interleukin-1 beta (IL-1 beta) from human peripheral blood mononuclear cells, a process that may contribute to atherogenesis. While 9-hydroxyoctadecadienoic acid (9-HODE) is a constituent of oxidized LDL and can by itself induce IL-1 beta release, its potency relative to oxidized LDL suggested that other components of modified LDL may also contribute to this phenomenon. In this study, LDL of varying oxidation states were prepared by altering the Cu2+ to LDL ratio and/or the length of oxidation. The oxidation status of LDL was measured as thiobarbituric acid reactive substances (TBARS), electrophoretic mobility in agarose gels, and the content of 9- and 13-HODE. High Cu2+ to LDL ratios promoted extensive TBARS formation and these LDL were the most potent activators of IL-1 beta release, although LDL with TBARS greater than 50 nmol/mg protein were cytotoxic and IL-1 beta release was diminished. An inverse correlation between HODE content and TBARS was found indicating lipid-derived aldehydes also contribute to IL-1 beta release by oxidized LDL. Accordingly, dialysis of oxidized LDL removed nearly all aldehydes and rendered the LDL unable to induce IL-1 beta release. The alkenals 2,4-decadienal and 2-octenal were tested and shown to induce IL-1 beta release while their saturated homologues had no effect. The predominant aldehyde in Cu(2+)-oxidized LDL was hexanal, with the unsaturated aldehydes 2,4-heptadienal, 2-octenal, and 2,4-decadienal also being present. These data indicate that multiple, lipid-derived species exist in oxidized LDL that can contribute to the release of IL-1 beta.
氧化型低密度脂蛋白（LDL）可诱导人外周血单核细胞释放白细胞介素-1β（IL-1β），这一过程可能与动脉粥样硬化的发生有关。虽然9-羟基十八碳二烯酸（9-HODE）是氧化型LDL的一种成分，其本身可诱导IL-1β释放，但其相对于氧化型LDL的效力表明，修饰型LDL的其他成分可能也参与了这一现象。在本研究中，通过改变Cu2+与LDL的比例和/或氧化时间制备了不同氧化状态的LDL。LDL的氧化状态通过硫代巴比妥酸反应性物质（TBARS）、琼脂糖凝胶中的电泳迁移率以及9-和13-HODE的含量来测定。高Cu2+与LDL比例促进了大量TBARS的形成，这些LDL是IL-1β释放的最有效激活剂，尽管TBARS大于50 nmol/mg蛋白的LDL具有细胞毒性，IL-1β释放减少。发现HODE含量与TBARS呈负相关，表明脂质衍生的醛也参与氧化型LDL诱导的IL-1β释放。因此，氧化型LDL的透析去除了几乎所有醛，使其无法诱导IL-1β释放。对2,4-癸二烯醛和2-辛烯醛进行了测试，结果表明它们可诱导IL-1β释放，而其饱和同系物则无此作用。Cu(2+)氧化型LDL中的主要醛是己醛，同时也存在不饱和醛2,4-庚二烯醛、2-辛烯醛和2,4-癸二烯醛。这些数据表明，氧化型LDL中存在多种脂质衍生成分，它们可促进IL-1β的释放。
