Ferulic acid prevents LPS-induced up-regulation of PDE4B and stimulates the cAMP/CREB signaling pathway in PC12 cells

Aim： Phosphodiesterase 4 （PDE4） isozymes are involved in different functions, depending on their patterns of distribution in the brain The PDE4 subtypes are distributed in different inflammatory cells, and appear to be important regulators of inflammatory processes. In this study we examined the eff...

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Published in:Acta pharmacologica Sinica 2016-12, Vol.37 (12), p.1543-1554
Main Authors: Huang, Hao, Hong, Qian, Tan, Hong-Ling, Xiao, Cheng-Rong, Gao, Yue
Format: Article
Language:English
Subjects:
Animals
cAMP反应元件结合蛋白
Coumaric Acids - pharmacology
CREB
Cyclic AMP - metabolism
Cyclic AMP Response Element-Binding Protein - metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism
Lipopolysaccharides - pharmacology
LPS
Molecular Docking Simulation
mRNA表达水平
Original
PC12 Cells
PC12细胞
Rats
Signal Transduction
Up-Regulation
信号通路
诱导
阿魏酸
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Summary:Aim： Phosphodiesterase 4 （PDE4） isozymes are involved in different functions, depending on their patterns of distribution in the brain The PDE4 subtypes are distributed in different inflammatory cells, and appear to be important regulators of inflammatory processes. In this study we examined the effects of ferulic acid （FA）, a plant component with strong anti-oxidant and anti-inflammatory activities, on lipopolysaccharide （LPS）-induced up-regulation of phosphodiesterase 4B （PDE4B） in PC12 cells, which in turn regulated cellular cAMP levels and the cAMP/cAMP response element binding protein （CREB） pathway in the cells. Methods： PC12 cells were treated with LPS （1 μg/mL） for 8 h, and the changes of F-actin were detected using laser scanning confocal microscopy. The levels of pro-inflammatory cytokines were measured suing ELISA kits, and PDE4B-specific enzymatic activity was assessed with a PDE413 assay kit. The mRNA levels of PDE4B were analyzed with Q-PCR, and the protein levels of CREB and phosphorylated CREB （pCREB） were determined using immunoblotting. Furthermore, molecular docking was used to identify the interaction between PDE4B2 and FA.Results： Treatment of PC12 cells with LPS induced thick bundles of actin filaments appearing in the F-actin cytoskeleton, which were ameliorated by pretreatment with FA （10-40 μmol/L） or with a PDE4B inhibitor rolipram （30 pmol/L）. Pretreatment with FA dose-dependently inhibited the LPS-induced production of TNF-α and IL-1β in PC12 cells. Furthermore, pretreatment with FA dosedependently attenuated the LPS-induced up-regulation of PDE4 activity in PC12 cells. Moreover, pretreatment with FA decreased LPS-induced up-regulation of the PDE4B mRNA, and reversed LPS-induced down-regulation of CREB and pCREB in PC12 cells. The molecular docking results revealed electrostatic and hydrophobic interactions between FA and PDE4B2. Conclusion： The beneficial effects of FA in PC12 cells might be conferred through inhibition of LPS-induced up-regulation of PDE4B and stimulation of cAMP/CREB signaling pathway. Therefore, FA may be a potential therapeutic intervention for the treatment of neuroinflammatory diseases such as AD.
ISSN:1671-4083
1745-7254
DOI:10.1038/aps.2016.88