Glycogen synthase kinase-3β regulates anti-inflammatory property of fluoxetine

Hui Chen Su, Ching Ting Ma, Bu Chin Yu, Yu Chieh Chien, Cheng Chieh Tsai, Wei Ching Huang, Chiou Feng Lin, Yeu Hui Chuang, Kung Chia Young, Jieh Neng Wang, Chiung Wen Tsao

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22 Citations (Scopus)

Abstract

A selective serotonin reuptake inhibitor fluoxetine not only is widely used in the treatment of depression but also has an anti-inflammatory property. Glycogen synthase kinase-3beta (GSK-3β) is a vital factor in the inflammation process. How fluoxetine interferes with inflammation via a GSK-3β-dependent pathway remains unclear. The aim of this study is to investigate the effects of fluoxetine on lipopolysaccharide (LPS)-induced inflammation. Results showed that fluoxetine decreased mortality rate of the mice. It also inhibited LPS-induced release of nitric oxide (NO) and prostaglandin E2 (PGE2) in serum and RAW264.7 murine macrophages and expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Upon LPS stimulation, fluoxetine caused a delay but increased in the phosphorylated levels of GSK-3β (ser9), whereas it did not affect LPS-induced activation of mitogen-activated protein kinase (MAPK) and generation of reactive oxygen species (ROS). Fluoxetine in combination with phosphatidylinositol 3-kinases/Akt inhibitors (LY294002 and Wortmannin) did not have a synergistic inhibition on LPS-induced NO release and PGE2 production. In addition, peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9622 showed no reverse effects of this inhibition of fluoxetine. GSK-3β knockdown blocked the inhibitory effects of fluoxetine on LPS-induced iNOS/NO release and COX-2/PGE2 production. These results indicated that GSK-3β regulated anti-inflammatory property of fluoxetine. However, Akt activation, ROS generation, and altered PPARγ activity were not involved in this inhibition of fluoxetine.

Original languageEnglish
Pages (from-to)150-156
Number of pages7
JournalInternational Immunopharmacology
Volume14
Issue number2
DOIs
Publication statusPublished - Oct 2012
Externally publishedYes

Keywords

  • COX-2/PGE2 production
  • Fluoxetine
  • GSK-3β
  • iNOS/NO release
  • Lipopolysaccharides

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Pharmacology

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  • Cite this

    Su, H. C., Ma, C. T., Yu, B. C., Chien, Y. C., Tsai, C. C., Huang, W. C., Lin, C. F., Chuang, Y. H., Young, K. C., Wang, J. N., & Tsao, C. W. (2012). Glycogen synthase kinase-3β regulates anti-inflammatory property of fluoxetine. International Immunopharmacology, 14(2), 150-156. https://doi.org/10.1016/j.intimp.2012.06.015