Cellular and Molecular Neurobiology

, Volume 39, Issue 2, pp 241–254 | Cite as

Retinoic Acid-Induced Protein 14 (RAI14) Promotes mTOR-Mediated Inflammation Under Inflammatory Stress and Chemical Hypoxia in a U87 Glioblastoma Cell Line

  • XiaoGang Shen
  • JiaRui Zhang
  • XiaoLong Zhang
  • YiFan Wang
  • YunFeng Hu
  • Jun GuoEmail author
Original Research


Retinoic acid-induced 14 is a developmentally regulated gene induced by retinoic acid and is closely associated with NIK/NF-κB signaling. In the present study, we examined the effect of RAI14 on mTOR-mediated glial inflammation in response to inflammatory factors and chemical ischemia. A U87 cell model of LPS- and TNF-α-induced inflammation was used to investigate the role of RAI14 in glial inflammation. U87 cells were treated with siR-RAI14 or everolimus to detect the correlation between mTOR, RAI14, and NF-κB. CoCl2-stimulated U87 cells were used to analyze the effect of RAI14 on mTOR-mediated NF-κB inflammatory signaling under chemical hypoxia. LPS and TNF-α stimulation resulted in the upregulation of RAI14 mRNA and protein levels in a dose- and time-dependent manner. RAI14 knockdown significantly attenuated the level of pro-inflammatory cytokine via inhibiting the IKK/NF-κB pathway. Treatment with an mTOR inhibitor (everolimus) ameliorated NF-κB activity and IKKα/β phosphorylation via RAI14 signaling. Notably, RAI14 also enhanced mTOR-mediated NF-κB activation under conditions of chemical hypoxia. These findings provide significant insight into the role of RAI14 in mTOR-induced glial inflammation, which is closely associated with infection and ischemia stimuli. Thus, RAI14 may be a potential drug target for the treatment of inflammatory diseases.


RAI14 Neuroinflmamation mTOR NF-κB Chemical hypoxia 



Eukaryotic initiation factor 4E binding protein1


Central nervous system


Cobalt chloride




Eukaryotic translational initiation factor 4 epsilon




NF-kappa-B inhibitor alpha


Nuclear factor NF-kappa-B inhibitor kinase




Messenger RNA


Mammalian target of rapamycin


Mammalian target of rapamycin complex


Nuclear factor kappa-light-chain-enhancer of activated B cells


NF-kappa-B-inducing kinase


Pathogen-associated molecular patterns


Phosphate-buffered saline


Retinoic acid-induced protein 14


Regulatory-associated protein of mTOR


Quantitative real-time polymerase chain reaction


Control siRNA.




Small interfering RNA


Toll-like receptors


Tumor-necrosis factor-α


Author Contributions

In this study, JG conceived the general idea. XGS, JRZ, XLZ, YFW, and YFH carried out experiments. XGS, and JG analyzed and interpreted the data and wrote the paper. JG critically reviewed and edited the work. All authors approved the final version of the manuscript.


This work was supported by Grants from the National Natural Science Foundation of China (81573409) and Natural Science Foundation of Jiangsu Province (BK20161574) and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Raditional Chinese and Western Medicine).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors. The manuscript does not contain clinical studies or patient data.

Supplementary material

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Supplementary material 1 (PDF 186 KB)
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Supplementary material 2 (PDF 161 KB)
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Supplementary material 6 (PDF 118 KB)
10571_2018_644_MOESM7_ESM.docx (63 kb)
Supplementary material 7 (DOCX 63 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • XiaoGang Shen
    • 1
    • 2
  • JiaRui Zhang
    • 1
    • 2
  • XiaoLong Zhang
    • 1
    • 2
  • YiFan Wang
    • 1
    • 2
  • YunFeng Hu
    • 1
    • 2
  • Jun Guo
    • 1
    • 2
    • 3
    Email author
  1. 1.State Key Laboratory Cultivation Base For TCM Quality and Efficacy, School of Medicine and Life ScienceNanjing University of Chinese MedicineNanjingPeople’s Republic of China
  2. 2.Key Laboratory of Drug Target and Drug for Degenerative DiseaseNanjing University of Chinese MedicineNanjingPeople’s Republic of China
  3. 3.Department of Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, School of Medicine and Life ScienceNanjing University of Chinese MedicineNanjingPeople’s Republic of China

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