Petrova T V, Akama K T, Van Eldik L J
Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611, USA.
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4668-73. doi: 10.1073/pnas.96.8.4668.
Mechanisms leading to down-regulation of activated microglia and astrocytes are poorly understood, in spite of the potentially detrimental role of activated glia in neurodegeneration. Prostaglandins, produced both by neurons and glia, may serve as mediators of glial and neuronal functions. We examined the influence of cyclopentenone prostaglandins and their precursors on activated glia. As models of glial activation, production of inducible nitric-oxide synthase (iNOS) was studied in lipopolysaccharide-stimulated rat microglia, a murine microglial cell line BV-2, and IL-1beta-stimulated rat astrocytes. Cyclopentenone prostaglandins were potent inhibitors of iNOS induction and were more effective than their precursors, prostaglandins E2 and D2. 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) was the most potent prostaglandin among those tested. In activated microglia, 15d-PGJ2 suppressed iNOS promoter activity, iNOS mRNA, and protein levels. The action of 15d-PGJ2 does not appear to involve its nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) because troglitazone, a specific ligand of PPARgamma, was unable to inhibit iNOS induction, and neither troglitazone nor 15d-PGJ2 could stimulate the activity of a PPAR-dependent promoter in the absence of cotransfected PPARgamma. 15d-PGJ2 did not block nuclear translocation or DNA-binding activity of the transcription factor NFkappaB, but it did inhibit the activity of an NFkappaB reporter construct, suggesting that the mechanism of suppression of microglial iNOS by 15d-PGJ2 may involve interference with NFkappaB transcriptional activity in the nucleus. Thus, our data suggest the existence of a novel pathway mediated by cyclopentenone prostaglandins, which may represent part of a feedback mechanism leading to the cessation of inflammatory glial responses in the brain.
尽管活化的神经胶质细胞在神经退行性变中可能具有有害作用，但导致活化的小胶质细胞和星形胶质细胞下调的机制仍知之甚少。神经元和神经胶质细胞都能产生前列腺素，它可能是神经胶质细胞和神经元功能的介质。我们研究了环戊烯酮前列腺素及其前体对活化神经胶质细胞的影响。作为神经胶质细胞活化的模型，我们在脂多糖刺激的大鼠小胶质细胞、小鼠小胶质细胞系BV-2以及白细胞介素-1β刺激的大鼠星形胶质细胞中研究了诱导型一氧化氮合酶（iNOS）的产生。环戊烯酮前列腺素是iNOS诱导的有效抑制剂，比其前体前列腺素E2和D2更有效。在测试的前列腺素中，15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2）是最有效的。在活化的小胶质细胞中，15d-PGJ2抑制iNOS启动子活性、iNOS mRNA和蛋白质水平。15d-PGJ2的作用似乎不涉及其核受体过氧化物酶体增殖物激活受体γ（PPARγ），因为PPARγ的特异性配体曲格列酮无法抑制iNOS诱导，并且在没有共转染PPARγ的情况下，曲格列酮和15d-PGJ2都不能刺激PPAR依赖性启动子的活性。15d-PGJ2没有阻断转录因子NFκB的核转位或DNA结合活性，但它确实抑制了NFκB报告基因构建体的活性，这表明15d-PGJ2抑制小胶质细胞iNOS的机制可能涉及干扰细胞核中NFκB的转录活性。因此，我们的数据表明存在一条由环戊烯酮前列腺素介导的新途径，这可能是导致大脑中炎症性神经胶质细胞反应停止的反馈机制的一部分。
