Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype.
Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype.
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DOI：
10.1186/1742-2094-7-3
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发表时间：
2010-01-14
影响因子：
9.3
通讯作者：
Langmann T
中科院分区：
文献类型：
--
作者：
Dirscherl K;Karlstetter M;Ebert S;Kraus D;Hlawatsch J;Walczak Y;Moehle C;Fuchshofer R;Langmann T
木犀草素是一种植物来源的黄酮类化合物，具有清除氧和氮的能力，具有多种药理活性和抗氧化性。木犀草素还通过抑制免疫细胞中的核因子kappaB(NFkB)信号而显示出强大的抗炎活性。为了更好地了解这种重要的类黄酮的免疫调节作用，我们对木犀草素处理的促炎挑战小胶质细胞进行了全基因组表达分析，并进行了表型和功能表征。用不同浓度的木犀草素处理静息和内毒素激活的BV-2小胶质细胞，检测促炎标志物的mRNA水平。DNA微阵列实验和生物信息数据挖掘被用来捕捉木犀草素刺激小胶质细胞后的整体转录变化。为了独立确认新发现的木犀草素调控的转录本，进行了广泛的qRT-PCR分析。用形态学方法评价木犀草素处理后小胶质细胞的活化状态。通过定量测定小胶质细胞条件培养液中661W光感受器分泌的一氧化氮水平和细胞凋亡来评价小胶质细胞介导的神经毒性。木犀草素剂量依赖性地抑制了脂多糖激活的小胶质细胞中促炎标志物的表达，并引发了小胶质细胞转录组的整体变化，有50多个差异表达的转录本。木犀草素可有效阻断促炎症和促凋亡基因的表达。相反，与抗氧化剂代谢、吞噬吸收、分支和趋化相关基因的mRNA水平显著诱导。木犀草素处理对小胶质细胞形态有重大影响，导致以前的阿米巴细胞的分支，并与长丝状足的形成有关。当木犀草素与小胶质细胞共同孵育时，内毒素激活的小胶质细胞在661W感光细胞上表现出强烈的NO分泌减少和明显的神经毒性。我们的研究结果证实了木犀草素对小胶质细胞促炎细胞因子表达的抑制作用。此外，我们的转录数据表明，这种类黄酮是一种有效的小胶质细胞激活调节剂，并影响几个信号通路，导致一种独特的表型，具有抗炎、抗氧化和神经保护特性。随着几个新的木犀草素调控基因的鉴定，我们的发现为理解木犀草素对小胶质细胞动态平衡的多种作用提供了分子基础。这些数据还表明，木犀草素有望成为治疗神经退行性疾病的免疫调节和神经保护疗法的候选药物。
Luteolin, a plant derived flavonoid, exerts a variety of pharmacological activities and anti-oxidant properties associated with its capacity to scavenge oxygen and nitrogen species. Luteolin also shows potent anti-inflammatory activities by inhibiting nuclear factor kappa B (NFkB) signaling in immune cells. To better understand the immuno-modulatory effects of this important flavonoid, we performed a genome-wide expression analysis in pro-inflammatory challenged microglia treated with luteolin and conducted a phenotypic and functional characterization. Resting and LPS-activated BV-2 microglia were treated with luteolin in various concentrations and mRNA levels of pro-inflammatory markers were determined. DNA microarray experiments and bioinformatic data mining were performed to capture global transcriptomic changes following luteolin stimulation of microglia. Extensive qRT-PCR analyses were carried out for an independent confirmation of newly identified luteolin-regulated transcripts. The activation state of luteolin-treated microglia was assessed by morphological characterization. Microglia-mediated neurotoxicity was assessed by quantifying secreted nitric oxide levels and apoptosis of 661W photoreceptors cultured in microglia-conditioned medium. Luteolin dose-dependently suppressed pro-inflammatory marker expression in LPS-activated microglia and triggered global changes in the microglial transcriptome with more than 50 differentially expressed transcripts. Pro-inflammatory and pro-apoptotic gene expression was effectively blocked by luteolin. In contrast, mRNA levels of genes related to anti-oxidant metabolism, phagocytic uptake, ramification, and chemotaxis were significantly induced. Luteolin treatment had a major effect on microglial morphology leading to ramification of formerly amoeboid cells associated with the formation of long filopodia. When co-incubated with luteolin, LPS-activated microglia showed strongly reduced NO secretion and significantly decreased neurotoxicity on 661W photoreceptor cultures. Our findings confirm the inhibitory effects of luteolin on pro-inflammatory cytokine expression in microglia. Moreover, our transcriptomic data suggest that this flavonoid is a potent modulator of microglial activation and affects several signaling pathways leading to a unique phenotype with anti-inflammatory, anti-oxidative, and neuroprotective characteristics. With the identification of several novel luteolin-regulated genes, our findings provide a molecular basis to understand the versatile effects of luteolin on microglial homeostasis. The data also suggest that luteolin could be a promising candidate to develop immuno-modulatory and neuroprotective therapies for the treatment of neurodegenerative disorders.
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影响因子：
6.1
作者：
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通讯作者：
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Rosenfeld, ME
影响因子：
5.3
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通讯作者：
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影响因子：
6
作者：
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通讯作者：
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