Colville-Nash P R, Qureshi S S, Willis D, Willoughby D A
Department of Experimental Pathology, St. Bartholomew's and The Royal London School of Medicine and Dentistry, United Kingdom.
J Immunol. 1998 Jul 15;161(2):978-84.
Genetic knock-out in mice of peroxisome proliferator-activated receptor-alpha (PPAR alpha) can prolong inflammation in response to leukotriene B4. Although cyclooxygenase 2 has been shown to be induced by PPAR activation, the effect of PPAR agonists on the key inflammatory enzyme systems of nitric oxide synthase (NOS) and stress proteins has not been investigated. The effect on these of naturally occurring eicosanoid PPAR agonists (leukotriene B4 and 8(S)-hydroxyeicosatetraenoic acid, which are PPAR alpha selective; PGA2, PGD2, PGJ2, and delta12PGJ2, which are PPAR gamma selective) and the synthetic PPAR alpha agonist Wy14,643 was examined in activated RAW264.7 murine macrophages. Leukotriene B4 and 8(S)-hydroxyeicosatetraenoic acid stimulated nitrite accumulation, indicative of enhanced NOS activity. PGA2, PGD2, PGJ2, delta12PGJ2, and Wy14,643 reduced nitrite accumulation, with delta12PGJ2 being the most effective. The mechanism behind this reduction was examined using Western blotting. Inhibition of nitrite accumulation was associated with a fall in inducible NOS protein and an induction of heme oxygenase 1, correlating both dose dependently and temporally. Other proteins examined (cyclooxygenase 2, heme oxygenase 2, heat shock protein 70, and glucose-regulated protein 78) were unaffected. The data suggest that naturally occurring PPAR agonists can inhibit the inducible NOS enzyme pathway. This inhibition may be mediated by modulation of the stress protein, heme oxygenase 1. Thus, the generation of eicosanoid breakdown products during inflammation may contribute to its eventual resolution by activation of the PPAR system. This system may thus represent a novel target for therapeutic intervention in inflammatory disease.
在小鼠中敲除过氧化物酶体增殖物激活受体α（PPARα）基因，可延长对白三烯B4的炎症反应。虽然已表明环氧合酶2可被PPAR激活所诱导，但尚未研究PPAR激动剂对一氧化氮合酶（NOS）和应激蛋白等关键炎症酶系统的影响。在活化的RAW264.7小鼠巨噬细胞中，检测了天然存在的类花生酸PPAR激动剂（对白三烯B4和8(S)-羟基二十碳四烯酸，它们对PPARα具有选择性；PGA2、PGD2、PGJ2和δ12PGJ2，它们对PPARγ具有选择性）以及合成的PPARα激动剂Wy14,643的作用。白三烯B4和8(S)-羟基二十碳四烯酸刺激亚硝酸盐积累，表明NOS活性增强。PGA2、PGD2、PGJ2、δ12PGJ2和Wy14,643可减少亚硝酸盐积累，其中δ12PGJ2最为有效。使用蛋白质印迹法研究了这种减少背后的机制。亚硝酸盐积累的抑制与诱导型NOS蛋白的减少和血红素加氧酶1的诱导有关，在剂量和时间上均呈依赖性相关。所检测的其他蛋白质（环氧合酶2、血红素加氧酶2、热休克蛋白70和葡萄糖调节蛋白78）未受影响。数据表明，天然存在的PPAR激动剂可抑制诱导型NOS酶途径。这种抑制可能是通过对应激蛋白血红素加氧酶1的调节介导的。因此，炎症过程中类花生酸分解产物的生成可能通过激活PPAR系统有助于炎症的最终消退。因此，该系统可能代表炎症性疾病治疗干预的一个新靶点。
