Li Zongmin, Jansen Marlon, Ogburn Kenyon, Salvatierra Laura, Hunter Lavonne, Mathew Sneha, Figueiredo-Pereira Maria E
Department of Biological Sciences, Hunter College of City University of New York, New York, New York 10021, USA.
J Neurosci Res. 2004 Dec 15;78(6):824-36. doi: 10.1002/jnr.20346.
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 up-regulation 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.
环氧化酶（COX-2）的促炎诱导形式在神经退行性变中的作用尚未明确界定。已知其一些代谢产物，如J2系列前列腺素（PG）具有神经毒性。在此我们证明，PGJ2可增强神经元细胞中COX-2基因表达，而不提高COX-1水平。PGJ2还增加了PGE2的产生，证实新合成的COX-2具有酶活性。PGJ2衍生物，如15d-PGJ2，是过氧化物酶体增殖物激活受体γ（PPARγ）的已知激活剂，PPARγ是一种激活基因表达的核受体。然而，选择性PPARγ激动剂吡格列酮未能上调COX-2，表明PGJ2对COX-2的作用不依赖PPARγ。此外，PGJ2可稳定IκBα水平，表明在这些条件下NFκB不具有活性。PGJ2对神经元NFκB活性的阻断可能是其神经毒性的一个重要因素，因为在中枢神经系统中，神经元存活似乎需要NFκB的反式激活。白细胞介素-1（IL1）是一种促炎细胞因子，已知可刺激与炎症相关的基因表达，包括COX-2。值得注意的是，PGJ2处理可增加神经元细胞中IL1的mRNA水平。促炎细胞因子可能通过p38丝裂原活化蛋白激酶（p38MAPK）而非JNK激活介导PGJ2诱导的COX-2上调，因为只有前者的抑制剂可阻止COX-2增加。硫醇还原剂，如N-乙酰半胱氨酸，可保护神经元细胞免受PGJ2的有害影响，而抗坏血酸则不能。总的来说，我们的研究结果表明，导致COX-2上调并伴随PGJ2产生的促炎状态通过PGJ2与COX-2之间的自毒循环启动了一种自我破坏机制，这可能会使神经退行性变加剧到无法逆转的程度。硫醇还原抗氧化剂可能为阻止这种神经退行性过程提供一种最佳策略。
