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. 2019 Mar;39(2):241-254. doi: 10.1007/s10571-018-0644-z. Epub 2018 Dec 15.


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.

Keywords: Chemical hypoxia; NF-κB; Neuroinflmamation; RAI14; mTOR.

MeSH terms

  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Cell Hypoxia / drug effects
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Everolimus / pharmacology
  • Gene Knockdown Techniques
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • I-kappa B Kinase / metabolism
  • Inflammation / metabolism*
  • Inflammation / pathology*
  • Inflammation Mediators / metabolism
  • Models, Biological
  • NF-kappa B / metabolism
  • Phosphorylation / drug effects
  • Protein Biosynthesis / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Stress, Physiological* / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects


  • Cytokines
  • Cytoskeletal Proteins
  • Inflammation Mediators
  • NF-kappa B
  • RAI14 protein, human
  • RNA, Messenger
  • Transcription Factors
  • Everolimus
  • TOR Serine-Threonine Kinases
  • I-kappa B Kinase