Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells.
Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells.
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DOI：
10.1371/journal.pone.0061462
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Vogel Z
中科院分区：
文献类型：
--
作者：
Juknat A;Pietr M;Kozela E;Rimmerman N;Levy R;Gao F;Coppola G;Geschwind D;Vogel Z
已知大麻素具有免疫抑制活性。然而，造成这些影响的机制尚不清楚。我们使用脂多糖 (LPS) 激活 BV-2 小胶质细胞，研究了大麻的主要精神活性成分 Δ9-四氢大麻酚 (THC) 和非精神活性成分大麻二酚 (CBD) 如何调节炎症反应。使用 Illumina 平台对全基因组 mRNA 水平进行微阵列分析，并使用 Ingenuity Pathway Analysis 分析所得表达模式，以识别基因的功能子集，并使用 Ingenuity System Database 来表示受 CBD 和 THC 调节的基因网络。在跨处理差异表达的 5338 个转录本中，发现 400 个转录本被 LPS 上调，502 个转录本被 CBD+LPS 上调，424 个转录本被 THC+LPS 上调，而 145 个转录本被 LPS 下调，297 个转录本被 CBD+LPS 下调，149 个转录本被 THC+LPS 下调，下调幅度为 2 倍或更多 (p≤0.005)。结果清楚地将 CBD 和 THC 的影响与炎症信号传导途径联系起来，并确定了 MAPK 途径（Dusp1、Dusp8、Dusp2）、细胞周期相关（Cdkn2b、Gadd45a）以及 JAK/STAT 调节分子（Socs3、Cish、Stat1）中的新大麻素靶标。 CBD 对 LPS 刺激的基因表达的影响大于 THC。我们将这种差异归因于 CBD 高度上调了编码 NFκB 和 AP-1 转录活性负调节因子的几个基因，例如已知通过 Nrf2 激活进行调节的 Trib3 和 Dusp1。 CBD 特异性表达谱反映了与氧化应激和谷胱甘肽通过 Trib3 消耗以及 ATF4 靶基因表达相关的变化。此外，CBD影响的基因被证明受到通常参与应激反应和炎症调节的核因子的控制，主要通过Nrf2/Hmox1轴和Nrf2/ATF4-Trib3途径。这些观察结果表明，CBD（以及较少的 THC）会诱导细胞应激反应，而这种反应是其高免疫抑制活性的基础。
Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS) to activate BV-2 microglial cells, we examined how Δ9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and cannabidiol (CBD) the non-psychoactive component, modulate the inflammatory response. Microarray analysis of genome-wide mRNA levels was performed using Illumina platform and the resulting expression patterns analyzed using the Ingenuity Pathway Analysis to identify functional subsets of genes, and the Ingenuity System Database to denote the gene networks regulated by CBD and THC. From the 5338 transcripts that were differentially expressed across treatments, 400 transcripts were found to be upregulated by LPS, 502 by CBD+LPS and 424 by THC+LPS, while 145 were downregulated by LPS, 297 by CBD+LPS and 149 by THC+LPS, by 2-fold or more (p≤0.005). Results clearly link the effects of CBD and THC to inflammatory signaling pathways and identify new cannabinoid targets in the MAPK pathway (Dusp1, Dusp8, Dusp2), cell cycle related (Cdkn2b, Gadd45a) as well as JAK/STAT regulatory molecules (Socs3, Cish, Stat1). The impact of CBD on LPS-stimulated gene expression was greater than that of THC. We attribute this difference to the fact that CBD highly upregulated several genes encoding negative regulators of both NFκB and AP-1 transcriptional activities, such as Trib3 and Dusp1 known to be modulated through Nrf2 activation. The CBD-specific expression profile reflected changes associated with oxidative stress and glutathione depletion via Trib3 and expression of ATF4 target genes. Furthermore, the CBD affected genes were shown to be controlled by nuclear factors usually involved in regulation of stress response and inflammation, mainly via Nrf2/Hmox1 axis and the Nrf2/ATF4-Trib3 pathway. These observations indicate that CBD, and less so THC, induce a cellular stress response and that this response underlies their high immunosuppressant activities.
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DOI：
10.1196/annals.1397.071
发表时间：
2007-01-01
期刊：
SIGNAL TRANSDUCTION PATHWAYS, PT D
影响因子：
--
作者：
Dos Santos, S.;Delattre, A.-I.;Raes, M.
通讯作者：
Raes, M.
影响因子：
3.3
作者：
Cabral, GA;Pettit, DAD
通讯作者：
Pettit, DAD
影响因子：
3.7
作者：
Esposito G;Scuderi C;Valenza M;Togna GI;Latina V;De Filippis D;Cipriano M;Carratù MR;Iuvone T;Steardo L
通讯作者：
Steardo L
影响因子：
14.8
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.
影响因子：
9.3
作者：
Banisor I;Leist TP;Kalman B
通讯作者：
Kalman B