Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation.
Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation.
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DOI：
10.1371/journal.pone.0069115
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
De Bosscher K
中科院分区：
文献类型：
--
作者：
Beck IM;Drebert ZJ;Hoya-Arias R;Bahar AA;Devos M;Clarisse D;Desmet S;Bougarne N;Ruttens B;Gossye V;Denecker G;Lievens S;Bracke M;Tavernier J;Declercq W;Gevaert K;Vanden Berghe W;Haegeman G;De Bosscher K
化合物A具有糖皮质激素受体（GR）依赖性抗炎性质。就像经典的GR配体一样，化合物A可以抑制NF-κ B介导的基因表达。然而，单体化合物A激活的GR不能触发糖皮质激素应答元件调节的基因表达。热休克反应有效地激活热休克因子1（HSF 1），上调热休克蛋白70，一种已知的GR分子伴侣，也调节炎症的各个方面。我们发现，选择性GR调节剂化合物A和热休克在A549肺上皮细胞中触发类似的细胞效应。关于它们的抗炎机制，热休克和化合物A都能够减少TNF-刺激的IκBα降解和NF-κB p65核转位。我们建立了化合物A激活的GR和Hsp 70之间的相互作用，但值得注意的是，尽管Hsp 70分子伴侣的存在本身对于化合物A介导的炎性基因抑制似乎是关键的，但随后的新Hsp 70蛋白合成与观察到的CpdA诱导的Hsp 70 mRNA上调解偶联，因此在介导CpdA的抗炎作用中是过时的。A549细胞中化合物A诱导的Hsp 70蛋白水平增加的缺乏不是由Hsp 70的快速蛋白酶体降解或由化合物A诱导的对翻译的一般阻断介导的。类似于热休克，化合物A可上调各种细胞系和BALB/c小鼠中Hsp 70基因的转录。有趣的是，尽管化合物A依赖性Hsp 70启动子激活是GR依赖性的但不依赖于HSF 1，但热休克诱导的Hsp 70表达在A549肺上皮细胞中以GR依赖性和HSF 1依赖性的方式交替发生。
Compound A possesses glucocorticoid receptor (GR)-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-κB-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1), upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti-inflammatory mechanism, heat shock and Compound A are both able to reduce TNF-stimulated IκBα degradation and NF-κB p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA’s anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A-induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR-dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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