IRON INDUCES LIPID-PEROXIDATION IN CULTURED MACROPHAGES, INCREASES THEIR ABILITY TO OXIDATIVELY MODIFY LDL, AND AFFECTS THEIR SECRETORY PROPERTIES
IRON INDUCES LIPID-PEROXIDATION IN CULTURED MACROPHAGES, INCREASES THEIR ABILITY TO OXIDATIVELY MODIFY LDL, AND AFFECTS THEIR SECRETORY PROPERTIES
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DOI：
10.1016/0021-9150(94)90192-9
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发表时间：
1994-11-01
期刊：
影响因子：
5.3
通讯作者：
AVIRAM, M
中科院分区：
文献类型：
--
作者：
FUHRMAN, B;OIKNINE, J;AVIRAM, M
本研究首次证明铁离子可以诱导完整巨噬细胞的脂质过氧化而不引起细胞死亡。巨噬细胞脂质过氧化增加细胞介导的LDL氧化，增强白细胞介素1的释放并抑制载脂蛋白E从巨噬细胞的释放。当培养的巨噬细胞暴露于亚铁离子（50 μ M FeSO4）在37 ℃下4小时，细胞脂质过氧化（通过分析丙二醛（MDA），共轭二烯（CD），和脂质过氧化物（PD））增加2 - 4倍，与未处理的细胞相比。这个过程是铁剂量依赖性的，在孵育4小时后达到最大值，并伴随着细胞亚油酸（18：2）和花生四烯酸（20：4）的含量分别减少68%和53%，细胞维生素E和维生素A分别减少29%和36%。细胞活力（通过台盼蓝拒染法、[H-3]胸苷掺入DNA、乳酸脱氢酶（LDH）或[H-3]腺嘌呤释放分析测定）和细胞形态（通过扫描电子显微镜研究）均未受到铁诱导的氧化应激的显著影响。甘露醇和二甲基硫脲（DMTU），而不是过氧化氢酶或超氧化物歧化酶（SOD），显着抑制铁诱导的细胞脂质过氧化物的形成，表明羟基自由基，而不是超氧化物或过氧化氢，介导的铁诱导的细胞脂质过氧化反应。LDL（0.2 mg蛋白/ml）与氧化巨噬细胞孵育导致LDL脂质过氧化，与在类似条件下与非氧化巨噬细胞孵育的LDL相比，LDL相关MDA增加8倍。此外，氧化的LDL的巨噬细胞在铜离子（10 μ M CuSO 4）的存在下的氧化是2倍高的LDL的氧化相比，由非氧化的巨噬细胞。氧化巨噬细胞释放的载脂蛋白E减少了50%，而巨噬细胞释放的β-葡萄糖醛酸苷酶和白细胞介素-1 β分别增加了83%和6倍。这项研究首次表明，铁离子诱导氧化的细胞多不饱和脂肪酸在完整的巨噬细胞，这种细胞脂质过氧化作用，随后可以诱导LDL氧化。
The present study demonstrates for the first time that iron ions can induce lipid peroxidation in intact macrophages without causing cell death. Macrophage lipid peroxidation increases cell-mediated oxidation of LDL, enhances the release of interleukin 1 and inhibits the release of apolipoprotein E from the macrophages. When cultured macrophages were exposed to ferrous ions (50 mu M FeSO4) for 4 h at 37 degrees C, cellular lipid peroxidation (measured by analyses of malondialdehyde (MDA), conjugated dienes (CD), and lipid peroxides (PD)) increased 2-4-fold in comparison with non-treated cells. This process was iron-dose dependent, reached its maximum after 4 h of incubation, and was accompanied by 68% and 53% reductions in the content of the cellular linoleic (18:2), and arachidonic acid (20:4), respectively, and by 29% and 36% reductions of cellular vitamin E and vitamin A, respectively. Cell viability (measured by trypan blue exclusion, by [H-3]thymidine incorporation into DNA, by analysis of the release of lactate dehydrogenase (LDH) or [H-3]adenine), and cell morphology (studied by scanning electron microscopy) were not significantly affected by the iron-induced oxidative stress. Manitol and dimethylthiourea (DMTU), but not catalase or superoxide dismutase (SOD), significantly inhibited iron-induced cellular lipid peroxide formation, suggesting that hydroxyl radical, but not superoxides or hydrogen peroxides, mediated the iron-induced cellular lipid peroxidation. Incubation of LDL (0.2 mg of protein/ml) with oxidized macrophages resulted in LDL lipids peroxidation, as evidenced by an 8-fold increase in the LDL associated MDA in comparison with LDL that was incubated under similar conditions with non-oxidized macrophages. Furthermore, oxidation of LDL by oxidized macrophages in the presence of copper ions (10 mu M CuSO4) was 2-fold higher in comparison with oxidation of LDL by non-oxidized macrophages. The release of apolipoprotein E from oxidized macrophages decreased by 50%, whereas macrophage release of beta-glucuronidase and of interleukin-1 beta increased by 83% and by a factor of 6, respectively. This study demonstrates for the first time that iron ions induce oxidation of the cellular polyunsaturated fatty acids in intact macrophages and that this cellular lipid peroxidation can subsequently induce LDL oxidation.