Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL-60612, United States.
Curr Alzheimer Res. 2018;15(10):894-904. doi: 10.2174/1567205015666180507104755.
Neuroinflammation plays an important role in the pathogenesis of various neurodegenerative diseases including Alzheimer's disease (AD). Suppressor of cytokine signaling 3 (SOCS3) is an anti-inflammatory molecule that suppresses cytokine signaling and inflammatory gene expression in different cells including microglia.
The pathways through which SOCS3 could be upregulated are poorly described. Cinnamic acid is a metabolite of cinnamon, a natural compound that is being widely used all over the world as a spice or flavoring agent. Here, we examined if cinnamic acid could upregulate SOCS3 in microglia.
Microglia and astroglia isolated from mouse brain as well as BV-2 microglial cells were treated with cinnamic acid followed by monitoring the level of SOCS3 and different proinflammatory molecules by RT-PCR and real-time PCR. To nail down the mechanism, we also performed ChIP analysis to monitore the recruitment of cAMP response element binding (CREB) to the socs3 gene promoter and carried out siRNA knockdown of CREB.
Cinnamic acid upregulated the expression of SOCS3 mRNA and protein in mouse BV-2 microglial cells in dose- and time-dependent manner. Accordingly, cinnamic acid also increased the level of SOCS3 and suppressed the expression of inducible nitric oxide synthase and proinflammatory cytokines (TNFα, IL-1β and IL-6) in LPSstimulated BV-2 microglial cells. Similar to BV-2 microglial cells, cinnamic acid also increased the expression of SOCS3 in primary mouse microglia and astrocytes. We have seen that cAMP response element is present in the promoter of socs3 gene, that cinnamic acid induces the activation of CREB, that siRNA knockdown of CREB abrogates cinnamic acid-mediated upregulation of SOCS3, and that cinnamic acid treatment leads to the recruitment of CREB to the socs3 gene.
These studies suggest that cinnamic acid upregulates the expression of SOCS3 in glial cells via CREB pathway, which may be of importance in neuroinflammatory and neurodegenerative disorders.
神经炎症在各种神经退行性疾病的发病机制中起着重要作用，包括阿尔茨海默病（AD）。细胞因子信号转导抑制因子 3（SOCS3）是一种抗炎分子，可抑制包括小胶质细胞在内的不同细胞中的细胞因子信号和炎症基因表达。
SOCS3 上调的途径描述甚少。肉桂酸是肉桂的一种代谢产物，肉桂是一种天然化合物，作为香料或调味剂在全世界广泛使用。在这里，我们研究了肉桂酸是否可以上调小胶质细胞中的 SOCS3。
用肉桂酸处理从小鼠脑中分离的小胶质细胞和星形胶质细胞以及 BV-2 小胶质细胞，然后通过 RT-PCR 和实时 PCR 监测 SOCS3 和不同促炎分子的水平。为了确定机制，我们还进行了 ChIP 分析，以监测 cAMP 反应元件结合（CREB）蛋白向 socs3 基因启动子的募集，并进行了 CREB 的 siRNA 敲低。
肉桂酸以剂量和时间依赖的方式上调小鼠 BV-2 小胶质细胞中 SOCS3 mRNA 和蛋白的表达。因此，肉桂酸还增加了 LPS 刺激的 BV-2 小胶质细胞中 SOCS3 的水平，并抑制了诱导型一氧化氮合酶和促炎细胞因子（TNFα、IL-1β 和 IL-6）的表达。与 BV-2 小胶质细胞类似，肉桂酸还增加了原代小鼠小胶质细胞和星形胶质细胞中 SOCS3 的表达。我们发现 socs3 基因启动子中存在 cAMP 反应元件，肉桂酸诱导 CREB 的激活，siRNA 敲低 CREB 可消除肉桂酸介导的 SOCS3 上调，肉桂酸处理导致 CREB 募集到 socs3 基因。
这些研究表明，肉桂酸通过 CREB 途径上调神经胶质细胞中 SOCS3 的表达，这在神经炎症和神经退行性疾病中可能很重要。
