title: AChE and RACK1 promote the anti-inflammatory properties of fluoxetine.
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.
authors.affiliation: Department of Biological Chemistry and The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Waiskopf
authors.forename: Keren
authors.initials: K
authors.lastname: Ofek
authors.forename: Adi
authors.initials: A
authors.lastname: Gilboa-Geffen
authors.forename: Uriya
authors.initials: U
authors.lastname: Bekenstein
authors.forename: Assaf
authors.initials: A
authors.lastname: Bahat
authors.forename: Estelle R
authors.initials: ER
authors.lastname: Bennett
authors.forename: Erez
authors.initials: E
authors.lastname: Podoly
authors.forename: Oded
authors.initials: O
authors.lastname: Livnah
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001665:Binding Sites; D005473:Fluoxetine / Q000494:pharmacology*; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D064546:Protein Kinase C beta / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000378:metabolism
chemical_list: D000110:Acetylcholinesterase; D000893:Anti-Inflammatory Agents; D005473:Fluoxetine; D058851:GPI-Linked Proteins; D019204:GTP-Binding Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009363:Neoplasm Proteins; D064546:Protein Kinase C beta; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D017367:Selective Serotonin Reuptake Inhibitors; D051197:Toll-Like Receptor 4; C419368:RACK1 protein, human; C495345:TLR4 protein, human; C548244:ACHE protein, human