Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase
Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase
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DOI：
10.1016/s0165-5728(99)00192-7
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发表时间：
1999-12-01
影响因子：
3.3
通讯作者：
Klockgether, T
中科院分区：
文献类型：
--
作者：
Heneka, MT;Feinstein, DL;Klockgether, T
小脑颗粒细胞（CGC）可表达诱导型一氧化氮合酶（iNOS），以响应炎症刺激。我们证明，诱导的诱导型一氧化氮合酶在CGCs的细菌脂多糖和促炎细胞因子的结果在细胞死亡，是由过量的L-精氨酸增强和抑制的选择性诱导型一氧化氮合酶抑制剂，2-氨基-二氢-6-甲基-4N-1，3-噻嗪。NO介导的细胞死亡伴随着caspase-3样活性增加、DNA断裂和阳性末端转移酶dUTP缺口末端标记（TUNEL），表明凋亡介导CGC细胞死亡。将CGCs与非甾体抗炎药（NSAID）、布洛芬或吲哚美辛或15-脱氧-δ（12，14）前列腺素J（2）（PGJ（2））孵育，可下调iNOS表达，并减少随后的细胞死亡。由于在其他细胞类型中，NSAID和PGJ（2）都可以激活过氧化物酶体增殖物激活受体γ（PPAR γ）并下调细胞因子水平和iNOS表达，并且由于CGC在体内和体外表达PPAR γ，我们的数据表明CGC PPAR γ的激活介导iNOS抑制和减少细胞死亡。由于PPARgamma在阿尔茨海默病（AD）患者的脑中表达，其中神经元iNOS表达和凋亡细胞死亡已被描述，这些结果可能有助于解释NSAID在PLD中的有益作用的基础。(C)1999 Elsevier Science B. V.保留所有权利。
Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-dihydro-6-methyl-4N-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-Delta(12,14) prostaglandin J(2) (PGJ(2)) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ(2) can activate the peroxisome proliferator-activated receptor-gamma (PPAR gamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPAR gamma in vivo and in vitro, our data suggest that activation of CGC PPAR gamma mediates iNOS suppression and reduced cell death. Because PPAR gamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in PLD. (C) 1999 Elsevier Science B.V. All rights reserved.