AChE and RACK1 promote the anti-inflammatory properties of fluoxetine

Nir Waiskopf, Keren Ofek, Adi Gilboa-Geffen, Uriya Bekenstein, Assaf Bahat, Estelle R. Bennett, Erez Podoly, Oded Livnah, Gunther Hartmann, Hermona Soreq*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Selective serotonin reuptake inhibitors (SSRIs) show anti-inflammatory effects, suggesting a possible interaction with both Toll-like-receptor 4 (TLR4) responses and cholinergic signaling through as yet unclear molecular mechanism(s). Our results of structural modeling support the concept that the antidepressant fluoxetine physically interacts with the TLR4-myeloid differentiation factor-2 complex at the same site as bacterial lipopolysaccharide (LPS). We also demonstrate reduced LPS-induced pro-inflammatory interleukin-6 and tumor necrosis factor alpha in human peripheral blood mononuclear cells preincubated with fluoxetine. Furthermore, we show that fluoxetine intercepts the LPS-induced decreases in intracellular acetylcholinesterase (AChE-S) and that AChE-S interacts with the nuclear factor kappa B (NFκB)-activating intracellular receptor for activated C kinase 1 (RACK1). This interaction may prevent NFκB activation by residual RACK1 and its interacting protein kinase PKCβII. Our findings attribute the anti-inflammatory properties of SSRI to surface membrane interference with leukocyte TLR4 activation accompanied by intracellular limitation of pathogen-inducible changes in AChE-S, RACK1, and PKCβII.

Original languageAmerican English
Pages (from-to)306-315
Number of pages10
JournalJournal of Molecular Neuroscience
Volume53
Issue number3
DOIs
StatePublished - Jun 2014

Bibliographical note

Funding Information:
Acknowledgments This work was supported by the Israel Science Foundation’s Legacy-Heritage-Biomedical Science Grant (no. 1876/11) (to HS). NW received a predoctoral fellowship from the Clara Robert Einstein Foundation and AG-G was supported by a FEBS postdoctoral fellowship for work in Bonn. HS and GH are members of the DFG Excellence Cluster ImmunoSensation.

Keywords

  • Acetylcholinesterase (AChE)
  • Antidepressant
  • Cholinergic
  • Inflammation
  • Receptor for activated C kinase 1 (RACK1)
  • Toll-like receptor

Fingerprint

Dive into the research topics of 'AChE and RACK1 promote the anti-inflammatory properties of fluoxetine'. Together they form a unique fingerprint.

Cite this