Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β.
Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β.
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DOI：
10.1016/j.nbd.2011.06.016
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发表时间：
2011-10
影响因子：
6.1
通讯作者：
Sandberg, Mats
中科院分区：
文献类型：
--
作者：
Correa, Fernando;Mallard, Carina;Nilsson, Michael;Sandberg, Mats
组蛋白去乙酰化酶（HDAC）抑制剂具有很好的神经保护和抗炎作用，但其确切机制尚不清楚。我们先前已经表明，脂多糖（LPS）激活的小胶质细胞因子可以下调星形胶质细胞核因子-红细胞2相关因子2（Nrf 2）诱导的抗氧化防御。在这里，我们评估了组蛋白修饰和GSK 3 β激活是否参与了小胶质细胞的这些负面影响。将小胶质细胞在无血清培养基中培养24小时以获得来自未活化细胞（MCM 0）的小胶质细胞条件培养基或用10 ng/mL LPS活化以产生MCM 10。用MCM 10处理的富含星形胶质细胞的培养物显示星形胶质细胞HDAC活性呈时间依赖性（0-72 h）增加，这与组蛋白H3和H4乙酰化水平降低以及转录因子Nrf 2和γ-谷氨酰半胱氨酸连接酶调节亚基（γGCL-M）蛋白水平降低相关。HDAC抑制剂丙戊酸（VPA）和阿司他汀-A（TSA）提高组蛋白乙酰化水平，恢复Nrf 2诱导的抗氧化防御，并在暴露于MCM 10的富含星形胶质细胞的培养物中保护免受氧化应激诱导的（H2 O2）死亡。GSK 3 β（锂）和p38 MAPK（SB 203580）信号通路的抑制剂恢复了受抑制的组蛋白乙酰化和Nrf 2相关转录，而Akt（Ly 294002）抑制剂导致Nrf 2相关转录进一步降低。总之，该研究表明，耐受性良好的药物如VPA和锂可以恢复Nrf 2诱导的抗氧化防御中的炎症诱导的抑制，可能是通过正常化的组蛋白乙酰化水平。
Histone deacetylase (HDAC) inhibitors have promising neuroprotective and anti-inflammatory properties although the exact mechanisms are unclear. We have earlier showed that factors from lipopolysaccharide (LPS)-activated microglia can down-regulate the astroglial nuclear factor-erythroid 2-related factor 2 (Nrf2)-inducible anti-oxidant defence. Here we have evaluated whether histone modification and activation of GSK3β are involved in these negative effects of microglia. Microglia were cultured for 24 h in serum-free culture medium to achieve microglia-conditioned medium from non-activated cells (MCM0) or activated with 10 ng/mL of LPS to produce MCM10. Astrocyte-rich cultures treated with MCM10 showed a time-dependent (0–72 h) increase in astroglial HDAC activity that correlated with lower levels of acetylation of histones H3 and H4 and decreased levels of the transcription factor Nrf2 and γ-glutamyl cysteine ligase modulatory subunit (γGCL-M) protein levels. The HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) elevated the histone acetylation levels, restored the Nrf2-inducible anti-oxidant defence and conferred protection from oxidative stress-induced (H2O2) death in astrocyte-rich cultures exposed to MCM10. Inhibitors of GSK3β (lithium) and p38 MAPK (SB203580) signaling pathways restored the depressed histone acetylation and Nrf2-related transcription whereas an inhibitor of Akt (Ly294002) caused a further decrease in Nrf2-related transcription. In conclusion, the study shows that well tolerated drugs such as VPA and lithium can restore an inflammatory induced depression in the Nrf2-inducible antioxidant defence, possibly via normalised histone acetylation levels.
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影响因子：
3.5
作者：
Goven, D.;Boutten, A.;Bonay, M.
通讯作者：
Bonay, M.
DOI：
10.1016/j.jss.2008.08.004
发表时间：
2010-04
期刊：
The Journal of surgical research
影响因子：
--
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Werstuck, GH
DOI：
10.1124/jpet.107.120188
发表时间：
2007-06-01
影响因子：
3.5
作者：
Kim, Hyeon Ju;Rowe, Michael;Chuang, De-Maw
通讯作者：
Chuang, De-Maw
影响因子：
4.8
作者：
Beurel, Eleonore;Jope, Richard S.
通讯作者：
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