Beharka Alison A, Wu Dayong, Serafini Mauro, Meydani Simin Nikbin
Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA.
Free Radic Biol Med. 2002 Mar 15;32(6):503-11. doi: 10.1016/s0891-5849(01)00817-6.
Vitamin E inhibits cyclooxygenase activity in macrophages from old mice by reducing peroxynitrite production. PGE(2) is a proinflammatory mediator that has been linked to a variety of age-associated diseases such as cancer, arthritis, and cardiovascular disease. Furthermore in the aged, increased cyclooxygenase (COX)-2-mediated PGE(2) production contributes to decline in T-cell-mediated function. Previously we reported that increased macrophage PGE(2) production in the aged is due to higher COX-2 activity and that supplementation with vitamin E significantly reduced the age-associated increase in macrophage PGE(2) production posttranslationally without changing COX-2 expression. Peroxynitrite, a product of nitric oxide (NO) and superoxide (O(-)(2)), increases the activity of COX without affecting its expression. Thus, we investigated if vitamin E inhibits COX activity through decreasing peroxynitrite formation. Macrophages from old mice had higher PGE(2) levels, COX activity, and NO levels than those from young mice, all of which were significantly reduced by vitamin E. When added individually, inhibitors of NO and O(-)(2) did not significantly reduce COX activity; however, when the inhibitors were combined, COX activity was significantly reduced in macrophages from old mice fed 30 ppm vitamin E. Increasing NO levels alone using SNAP or O(-)(2) levels, using X/XO, had no effect; however, increasing peroxynitrite levels using Sin-1 or X/XO + SNAP significantly increased COX activity in macrophages from old mice fed 500, but not those fed 30 ppm vitamin E. These data strongly suggest that peroxynitrite plays an important role in the vitamin E-induced inhibition of COX activity. These findings have important implications for designing interventions to reverse and/or delay age-associated dysregulation of immune and inflammatory responses and diseases associated with them.
维生素E通过减少过氧亚硝酸盐的产生来抑制老年小鼠巨噬细胞中的环氧化酶活性。前列腺素E2（PGE2）是一种促炎介质，与多种与年龄相关的疾病有关，如癌症、关节炎和心血管疾病。此外，在老年人中，环氧化酶（COX）-2介导的PGE2产生增加会导致T细胞介导功能下降。此前我们报道，老年人巨噬细胞中PGE2产生增加是由于COX-2活性较高，补充维生素E可在翻译后显著降低与年龄相关的巨噬细胞PGE2产生增加，而不改变COX-2表达。过氧亚硝酸盐是一氧化氮（NO）和超氧阴离子（O2-）的产物，可增加COX的活性而不影响其表达。因此，我们研究了维生素E是否通过减少过氧亚硝酸盐的形成来抑制COX活性。老年小鼠的巨噬细胞比年轻小鼠的巨噬细胞具有更高的PGE2水平、COX活性和NO水平，而维生素E可使所有这些水平显著降低。单独添加时，NO和O2-的抑制剂不会显著降低COX活性；然而，当将抑制剂联合使用时，喂食30 ppm维生素E的老年小鼠巨噬细胞中的COX活性显著降低。单独使用硝普钠（SNAP）增加NO水平或使用黄嘌呤/黄嘌呤氧化酶（X/XO）增加O2-水平均无效果；然而，使用S-亚硝基谷胱甘肽（Sin-1）或X/XO + SNAP增加过氧亚硝酸盐水平可显著增加喂食500 ppm维生素E的老年小鼠巨噬细胞中的COX活性，但对喂食30 ppm维生素E的小鼠巨噬细胞则无此作用。这些数据强烈表明，过氧亚硝酸盐在维生素E诱导的COX活性抑制中起重要作用。这些发现对于设计干预措施以逆转和/或延缓与年龄相关的免疫和炎症反应失调以及与之相关的疾病具有重要意义。
