Mechanism of age-associated up-regulation in macrophage PGE2 synthesis.
Mechanism of age-associated up-regulation in macrophage PGE2 synthesis.
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巨噬细胞 PGE2 合成中年龄相关上调的机制。
DOI：
10.1016/j.bbi.2004.05.003
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Meydani,SiminNikbin
中科院分区：
文献类型：
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作者：
Wu,Dayong;Meydani,SiminNikbin
在衰老过程中，身体的许多生理功能发生了变化。失调的免疫和炎症反应在人类和动物中都有很好的记录。对这些疾病的细胞和分子机制的研究提供了令人信服的证据，表明环氧化酶(COX)-2及其产物，特别是前列腺素（PG）E2，在年龄相关的免疫和炎症反应失调中起着关键作用。特别是，一些研究表明，随着年龄的增长，老年巨噬细胞（Mφ）中pge2的产生增加有助于抑制T细胞功能。此外，针对减少pge2生成的干预措施已被证明可以增强T细胞介导的功能。COX-2及其催化产物也被认为在阿尔茨海默病和帕金森病等与年龄相关的神经退行性疾病中发挥关键作用。一些研究人员已经证明，使用抑制COX活性的抗炎药物对预防和治疗这些疾病是有益的。因此，了解年龄相关的COX-2上调的潜在机制并描述导致这种年龄相关变化的因素是很重要的。本文就pge2在小鼠Mφ中的调控作用作一综述；COX-2表达的年龄相关性变化；以及它对老年免疫系统和大脑中某些疾病的影响。pge2生成的增加主要是由于COX活性的增加，而COX活性的增加又是由于COX-2蛋白和mRNA表达的增加。升高的COX-2 mRNA代表更高的转录率，而不是COX-2 mRNA稳定性的改变。在刺激下，老年小鼠的Mφ比年轻小鼠产生更多的神经酰胺（一种神经脂）。神经酰胺已被证明可以诱导和增强lps刺激的COX-2表达和pge2的产生。一些证据表明，老年Mφ中较高的神经酰胺水平是与年龄相关的Mφ中COX-2上调的重要因素。神经酰胺通过增加转录因子NF-κB的激活而上调COX-2的转录。进一步了解COX-2上调的分子机制将有助于描述导致老年人免疫和神经疾病发展的基本年龄相关变化。
Many physiological functions of the body change during the aging process. Dysregulated immune and inflammatory responses have been well documented in both humans and animals. The investigation into the cellular and molecular mechanism underlying these disorders has provided compelling evidence that up-regulated cyclooxygenase (COX)-2 and its product, particularly prostaglandin (PG)E2, play a critical role in the age-associated dysregulation of the immune and inflammatory responses. In particular, several studies have shown that increased PGE2production in old macrophages (Mφ) contributes to the suppression of T cell function with aging. Furthermore, interventions targeted at decreasing PGE2production have been shown to enhance T cell-mediated function. COX-2 and its catalytic products are also suggested to play a key role in age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Administration of anti-inflammatory drugs which inhibit COX activity has been shown, by some investigators, to be beneficial in preventing and treating these diseases. It is, thus, important to understand the underlying mechanisms of age-related COX-2 up-regulation and to delineate the factors, which contribute to this age-related change. This review focuses on the regulation of PGE2production in murine Mφ; the age-associated changes in COX-2 expression; and its implication for certain disorders observed in the aged immune system and brain. Increased PGE2production has been shown to be mainly due to an increase in COX activity, which is, in turn, due to an increase in COX-2 protein and mRNA expression. Elevated COX-2 mRNA represents a higher transcription rate rather than an altered stability of COX-2 mRNA. Upon stimulation, Mφ from old mice generate more ceramide, a sphingolipid, than those from young mice. Ceramide has been shown to induce, by itself, and also augment, LPS-stimulated COX-2 expression and PGE2production. Several lines of evidence indicate that the higher ceramide levels in old Mφ are an important contributor to the age-associated up-regulation of COX-2 in Mφ. Ceramide up-regulates COX-2 transcription by increasing activation of transcription factor NF-κB. Further understanding of molecular mechanisms involved in COX-2 up-regulation will help in delineating fundamental age-related changes, which lead to the development of immune and neurological disorders in the aged.