Abstract
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.
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Abbreviations
- 4EBP1:
-
Eukaryotic initiation factor 4E binding protein1
- CNS:
-
Central nervous system
- CoCl2 :
-
Cobalt chloride
- Co-IP:
-
Co-immunoprecipitation
- eIF4E:
-
Eukaryotic translational initiation factor 4 epsilon
- Evero:
-
Everolimus
- IκB-α:
-
NF-kappa-B inhibitor alpha
- IKK:
-
Nuclear factor NF-kappa-B inhibitor kinase
- LPS:
-
Lipopolysaccharide
- mRNA:
-
Messenger RNA
- mTOR:
-
Mammalian target of rapamycin
- mTORC:
-
Mammalian target of rapamycin complex
- NF-κB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- NIK:
-
NF-kappa-B-inducing kinase
- PAMPs:
-
Pathogen-associated molecular patterns
- PBS:
-
Phosphate-buffered saline
- RAI14:
-
Retinoic acid-induced protein 14
- Raptor:
-
Regulatory-associated protein of mTOR
- RT-qPCR:
-
Quantitative real-time polymerase chain reaction
- si-NC:
-
Control siRNA.
- siR-RAI14:
-
RAI14 siRNA
- siRNA:
-
Small interfering RNA
- TLRs:
-
Toll-like receptors
- TNF-α:
-
Tumor-necrosis factor-α
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Funding
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).
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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.
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Shen, X., Zhang, J., Zhang, X. et al. Retinoic Acid-Induced Protein 14 (RAI14) Promotes mTOR-Mediated Inflammation Under Inflammatory Stress and Chemical Hypoxia in a U87 Glioblastoma Cell Line. Cell Mol Neurobiol 39, 241–254 (2019). https://doi.org/10.1007/s10571-018-0644-z
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DOI: https://doi.org/10.1007/s10571-018-0644-z