Neurotoxic prostaglandin J2 enhances cyclooxygenase-2 expression in neuronal cells through the p38MAPK pathway: A death wish?
Neurotoxic prostaglandin J2 enhances cyclooxygenase-2 expression in neuronal cells through the p38MAPK pathway: A death wish?
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DOI：
10.1002/jnr.20346
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发表时间：
2004-12-15
影响因子：
4.2
通讯作者：
Figueiredo-Pereira, ME
中科院分区：
文献类型：
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作者：
Li, ZM;Jansen, M;Figueiredo-Pereira, ME
促炎症和诱导型环氧合酶(COX-2)在神经退行性变中的作用尚不清楚。它的一些代谢产品，如J2系列的前列腺素(PG)，已知是神经毒性的。在这里，我们证明了PGJ2增强了神经细胞中COX-2基因的表达，而不会提高COX-1的水平。PGJ2还增加了PGE2的产量，证明从头合成的COX-2具有酶活性。PGJ2衍生物，如15d-PGJ2，是已知的PPARGamma的激活剂，PPARGamma是一种激活基因表达的核受体。然而，选择性PPARγ激动剂西格列酮不能上调COX-2，表明PGJ2对COX-2的作用不依赖于PPARγ。此外，PGJ2稳定了IkappaBalpha的水平，表明NFkappaB在这些条件下不活跃。PGJ2对神经元NFkappaB活性的阻断可能是其神经毒性的一个重要因素，因为NFkappaB的反式激活似乎是中枢神经系统神经元生存所必需的。白介素1(IL1)是一种促炎细胞因子，可刺激炎症相关基因的表达，包括COX-2。值得注意的是，经PGJ2处理后，神经细胞中IL1mRNA水平升高。促炎症细胞因子可能通过p38MAPK介导PGJ2上调COX-2，而不是通过JNK激活，因为前者只有一种抑制剂能阻止COX-2的上调。硫醇还原剂，如N-乙酰半胱氨酸，保护神经细胞免受PGJ2的有害影响，而抗坏血酸则不起作用。总而言之，我们的发现表明，导致COX-2上调的促炎条件以及伴随而来的PGJ2的产生，通过PGJ2和COX-2之间的自毒循环启动了一种自我毁灭的机制，可能会加剧神经退行性变，超过无可救药的程度。减少硫醇的抗氧化剂可能会提供一种阻止这种神经退化过程的最佳策略。(C)2004年Wiley-Liss公司
The role of the proinflammatory and inducible form of cyclooxygenases (COX-2) in neurodegeneration is not well defined. Some of its metabolic products, such as prostaglandins (PG) of the J2 series, are known to be neurotoxic. Here we demonstrate that PGJ2 enhances COX-2 gene expression without elevating COX-1 levels in neuronal cells. PGJ2 also increased PGE2 production, establishing that the de novo synthesized COX-2 is enzymatically active. PGJ2 derivatives, such as 15d-PGJ2, are known activators of PPARgamma, a nuclear receptor that activates gene expression. However, the selective PPARgamma agonist ciglitazone failed to up-regulate COX-2, indicating that the PGJ2 effect on COX-2 is PPARgamma independent. Furthermore, PGJ2 stabilized IkappaBalpha levels, indicating that NFkappaB is not active under these conditions. The blocking of neuronal NFkappaB activity by PGJ2 may be an important contributor to its neurotoxicity, insofar as NFkappaB transactivation seems to be required for neuronal survival in the CNS. Interleukin-1 (IL1) is a proinflammatory cytokine known to stimulate the expression of genes associated with inflammation, including COX-2. Notably, IL1 mRNA levels in the neuronal cells were increased by PGJ2 treatment. The proinflammatory cytokine may mediate COX-2 up-regulation by PGJ2 through p38MAPK and not JNK activation, in that only an inhibitor of the former prevented the COX-2 increase. Thiol-reducing agents, such as N-acetylcysteine, protected the neuronal cells from the deleterious effects of PGJ2, whereas ascorbic acid did not. Collectively, our findings suggest that proinflammatory conditions that lead to COX-2 upregulation and the concomitant production of PGJ2 initiate a mechanism of self-destruction through an autotoxic loop between PGJ2 and COX-2 that may exacerbate neurodegeneration beyond a point of no return. Thiol-reducing antioxidants may offer an optimal strategy for halting this neurodegenerative process. (C) 2004 Wiley-Liss, Inc.