Pristimerin Inhibits LPS-Triggered Neurotoxicity in BV-2 Microglia Cells Through Modulating IRAK1/TRAF6/TAK1-Mediated NF-κB and AP-1 Signaling Pathways In Vitro

Hui, Bin; Zhang, Liping; Zhou, Qinhua; Hui, Ling

doi:10.1007/s12640-017-9837-3

ORIGINAL ARTICLE
Published: 08 November 2017

Pristimerin Inhibits LPS-Triggered Neurotoxicity in BV-2 Microglia Cells Through Modulating IRAK1/TRAF6/TAK1-Mediated NF-κB and AP-1 Signaling Pathways In Vitro

Bin Hui¹^na1,
Liping Zhang²^na1,
Qinhua Zhou^1,3 &
Ling Hui⁴

Neurotoxicity Research volume 33, pages 268–283 (2018)Cite this article

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Abstract

Microglia plays a prominent role in the brain’s inflammatory response to injury or infection by migrating to affected locations and secreting inflammatory molecules. However, hyperactivated microglial is neurotoxic and plays critical roles in the pathogenesis of neurodegenerative diseases. Pristimerin, a naturally occurring triterpenoid, possesses antitumor, antioxidant, and anti-inflammatory activities. However, the effect and the molecular mechanism of pristimerin against lipopolysaccharide (LPS)-induced neurotoxicity in microglia remain to be revealed. In the present study, using BV-2 microglial cultures, we investigated whether pristimerin modifies neurotoxicity after LPS stimulation and which intracellular pathways are involved in the effect of pristimerin. Here we show that pristimerin markedly suppressed the release of Regulated on Activation, Normal T Expressed and Secreted (RANTES), transforming growth factor-β1 (TGF-β1), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO). Pristimerin also significantly inhibited migration of BV-2 microglia and alleviated the death of neuron-like PC12 cell induced by the conditioned medium from LPS-activated BV-2 microglial cells. Moreover, pristimerin reduced the expression and interaction of TNF Receptor-Associated Factor 6 (TRAF6) and Interleukin-1 Receptor-Associated Kinases (IRAK1), limiting TGF-beta activating kinase 1 (TAK1) activation, and resulting in an inhibition of IKKα/β/NF-κB and MKK7/JNK/AP-1 signaling pathway in LPS-activated BV-2 microglia. Taken together, the anti-neurotoxicity action of pristimerin is mediated through the inhibition of TRAF6/IRAK1/TAK1 interaction as well as the related pathways: IKKα/β/NF-κB and MKK7/JNK/AP-1 signaling pathways. These findings may suggest that pristimerin might serve as a new therapeutic agent for treating hyperactivated microglial induced neurodegenerative diseases.

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Acknowledgements

We are grateful to Professor Geng Meiyu (Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China) for kindly providing us with PC12 cells. We also are grateful to Professor Guo Su (Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA) for critically editing the paper.

Funding

This study was supported by the Foundation of Shanghai University of Medicine & Health Sciences (HMSF-16-21-007 and JW-2014ZZBJ-px(YX)-GY01) and the National Natural Science Foundation of China (81372177).

Author information

Bin Hui and Liping Zhang contributed equally to this work.

Affiliations

College of Pharmacy, Shanghai University of Medical & Health Sciences, Shanghai, China
Bin Hui & Qinhua Zhou
Department of Emergency Medicine, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
Liping Zhang
Department of Pharmacology, College of Medicine, Jiaxing University, Jiaxing, China
Qinhua Zhou
Center for Experimental Medicine, Lanzhou Military Command, Lanzhou General Hospital, Lanzhou, Gansu, China
Ling Hui

Authors

Bin Hui
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Liping Zhang
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Qinhua Zhou
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Ling Hui
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Contributions

Bin Hui, Liping Zhang, and Qinhua Zhou designed the experiments; Bin Hui, Qinhua Zhou, Liping Zhang, and Ling Hui performed parts of the experiments; Bin Hui, Qinhua Zhou, and Liping Zhang analyzed the data; Bin Hui, Qinhua Zhou, and Liping Zhang wrote the manuscript.

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Correspondence to Qinhua Zhou.

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Hui, B., Zhang, L., Zhou, Q. et al. Pristimerin Inhibits LPS-Triggered Neurotoxicity in BV-2 Microglia Cells Through Modulating IRAK1/TRAF6/TAK1-Mediated NF-κB and AP-1 Signaling Pathways In Vitro. Neurotox Res 33, 268–283 (2018). https://doi.org/10.1007/s12640-017-9837-3

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Received: 09 April 2017
Revised: 24 September 2017
Accepted: 20 October 2017
Published: 08 November 2017
Issue Date: February 2018
DOI: https://doi.org/10.1007/s12640-017-9837-3

Keywords

Pristimerin
Neuroinflammation
Neurotoxicity
IRAK1
TRAF6
TAK1