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Gemfibrozil, a Lipid-Lowering Drug, Upregulates IL-1 Receptor Antagonist in Mouse Cortical Neurons: Implications for Neuronal Self-Defense

Corbett, Grant T, Roy, Avik, Pahan, Kalipada·2012·The Journal of Immunology
DOI 10.4049/jimmunol.1102624PMC PMC3523125
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Abstract

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.

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Metadata

Authors
Corbett, G. T., Roy, A., & Pahan, K.
Affiliations
  • Graduate Program in Neuroscience, Department of Neurological Sciences, Rush University Medical Center , Chicago, IL 60612
  • Department of Neurological Sciences, Rush University Medical Center , Chicago, IL 60612
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2012-07
Volume
189
Issue
2
Pages
1002-1013
ISSN
  • 0022-1767
  • 1550-6606
DOI
10.4049/jimmunol.1102624
PMC
PMC3523125
Cited by
54
References
7
Language
en
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)

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