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

Research output: Contribution to journalArticlepeer-review

23 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 - 2012 Oct 1

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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