AChE and RACK1 Promote the Anti-inflammatory Properties of Fluoxetine

Overview

Journal J Mol Neurosci

Specialties Molecular Biology
Neurology

Date 2013 Nov 22

PMID 24258317

Citations 15

Authors

Nir Waiskopf

Keren Ofek

Adi Gilboa-Geffen

Uriya Bekenstein

Assaf Bahat

Estelle R Bennett

Erez Podoly

Oded Livnah

Gunther Hartmann

Hermona Soreq

Affiliations

Soon will be listed here.

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.

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