Hayek M G, Mura C, Wu D, Beharka A A, Han S N, Paulson K E, Hwang D, Meydani S N
Nutritional Immunology Laboratory, Sackler Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
J Immunol. 1997 Sep 1;159(5):2445-51.
Macrophages (Mphi) from old mice produce more PGE2 than those from young mice, contributing to the dysregulation of the immune and inflammatory responses with age. This study was conducted to determine the mechanisms of the age-associated increase in Mphi PGE2 production. PGE2 production is influenced by the availability of the substrate arachidonic acid and by activity of the enzyme cyclooxygenase (Cox). We demonstrate that when the substrate is not the limiting factor, Mphi from old mice have significantly higher LPS-stimulated Cox activity than young mice, indicating that the age-associated increase in PGE2 production is due to increased enzyme activity and not to changes in substrate level. Cox activity is determined by the enzyme level and requires hydroperoxide for activation. Of the two Cox isoforms, Cox 1 is constitutively expressed in nearly all cells; whereas Cox 2 is induced by a wide range of ligands. Analysis of accumulated and de novo synthesis of constitutive Cox 1 and inducible Cox 2 proteins showed no age-related difference in Cox 1 protein levels, but Mphi from old mice had higher accumulated and newly synthesized LPS-stimulated Cox 2 protein levels than young mice. Furthermore, Mphi from old mice had higher LPS-stimulated levels of Cox 2 mRNA compared with those from young mice. Clearly, the age-associated increase in LPS-stimulated PGE2 production is due to increased Cox activity resulting from higher Cox 2 protein and mRNA expression. These findings have significant implications for age-associated immune and inflammatory dysregulation as well as the development of preventive and therapeutic strategies against them.
老年小鼠的巨噬细胞（Mphi）比幼年小鼠的巨噬细胞产生更多的前列腺素E2（PGE2），这导致了随着年龄增长免疫和炎症反应的失调。本研究旨在确定与年龄相关的Mphi中PGE2产生增加的机制。PGE2的产生受底物花生四烯酸的可用性以及环氧化酶（Cox）活性的影响。我们证明，当底物不是限制因素时，老年小鼠的Mphi在脂多糖（LPS）刺激下的Cox活性显著高于幼年小鼠，这表明与年龄相关的PGE2产生增加是由于酶活性增加，而非底物水平的变化。Cox活性由酶水平决定，且需要氢过氧化物激活。在两种Cox同工型中，Cox 1在几乎所有细胞中组成性表达；而Cox 2则由多种配体诱导。对组成性Cox 1和诱导性Cox 2蛋白的积累和从头合成分析表明，Cox 1蛋白水平没有年龄相关差异，但老年小鼠的Mphi中LPS刺激后的Cox 2蛋白积累水平和新合成水平均高于幼年小鼠。此外，与幼年小鼠的Mphi相比，老年小鼠的Mphi在LPS刺激下的Cox 2 mRNA水平更高。显然，与年龄相关的LPS刺激下PGE2产生增加是由于Cox 2蛋白和mRNA表达增加导致的Cox活性增强。这些发现对于与年龄相关的免疫和炎症失调以及针对它们的预防和治疗策略的开发具有重要意义。
