Gemfibrozil, a lipid-lowering drug, upregulates IL-1 receptor antagonist in mouse cortical neurons: implications for neuronal self-defense

J Immunol. 2012 Jul 15;189(2):1002-13. doi: 10.4049/jimmunol.1102624. Epub 2012 Jun 15.


Chronic inflammation is becoming a hallmark of several neurodegenerative disorders and accordingly, IL-1β, a proinflammatory cytokine, is implicated in the pathogenesis of neurodegenerative diseases. Although IL-1β binds to its high-affinity receptor, IL-1R, and upregulates proinflammatory signaling pathways, IL-1R antagonist (IL-1Ra) adheres to the same receptor and inhibits proinflammatory cell signaling. Therefore, upregulation of IL-1Ra is considered important in attenuating inflammation. The present study underlines a novel application of gemfibrozil (gem), a Food and Drug Administration-approved lipid-lowering drug, in increasing the expression of IL-1Ra in primary mouse and human neurons. Gem alone induced an early and pronounced increase in the expression of IL-1Ra in primary mouse cortical neurons. Activation of type IA p110α PI3K and Akt by gem and abrogation of gem-induced upregulation of IL-1Ra by inhibitors of PI3K and Akt indicate a role of the PI3K-Akt pathway in the upregulation of IL-1Ra. Gem also induced the activation of CREB via the PI3K-Akt pathway, and small interfering RNA attenuation of CREB abolished the gem-mediated increase in IL-1Ra. Furthermore, gem was able to protect neurons from IL-1β insult. However, small interfering RNA knockdown of neuronal IL-1Ra abrogated the protective effect of gem against IL-1β, suggesting that this drug increases the defense mechanism of cortical neurons via upregulation of IL-1Ra. Taken together, these results highlight the importance of the PI3K-Akt-CREB pathway in mediating gem-induced upregulation of IL-1Ra in neurons and suggest gem as a possible therapeutic treatment for propagating neuronal self-defense in neuroinflammatory and neurodegenerative disorders.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / physiology
  • Apoptosis Regulatory Proteins / therapeutic use
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / immunology*
  • Gemfibrozil / therapeutic use*
  • Humans
  • Hypolipidemic Agents / therapeutic use*
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / physiology
  • Inflammation Mediators / therapeutic use
  • Interleukin 1 Receptor Antagonist Protein / biosynthesis*
  • Interleukin 1 Receptor Antagonist Protein / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / immunology
  • Neurodegenerative Diseases / pathology
  • Neurons / enzymology
  • Neurons / immunology*
  • Neurons / pathology
  • Phosphatidylinositol 3-Kinase / physiology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Up-Regulation / drug effects
  • Up-Regulation / immunology*


  • Apoptosis Regulatory Proteins
  • Hypolipidemic Agents
  • Inflammation Mediators
  • Interleukin 1 Receptor Antagonist Protein
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Gemfibrozil