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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / chemistry
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Acetylcholinesterase / metabolism*
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Amino Acid Sequence
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Anti-Inflammatory Agents / pharmacology*
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Binding Sites
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Fluoxetine / pharmacology*
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GPI-Linked Proteins / chemistry
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GPI-Linked Proteins / metabolism
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GTP-Binding Proteins / chemistry
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GTP-Binding Proteins / metabolism*
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Humans
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Lipopolysaccharides / pharmacology
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Molecular Docking Simulation
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Molecular Sequence Data
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Monocytes / drug effects
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Monocytes / metabolism
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / metabolism*
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Protein Binding
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Protein Kinase C beta / metabolism
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Receptors for Activated C Kinase
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Receptors, Cell Surface / chemistry
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Receptors, Cell Surface / metabolism*
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Selective Serotonin Reuptake Inhibitors / pharmacology*
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Toll-Like Receptor 4 / chemistry
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Toll-Like Receptor 4 / metabolism
Substances
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Anti-Inflammatory Agents
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GPI-Linked Proteins
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Interleukin-6
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Lipopolysaccharides
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Neoplasm Proteins
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RACK1 protein, human
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Receptors for Activated C Kinase
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Receptors, Cell Surface
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Serotonin Uptake Inhibitors
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TLR4 protein, human
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Toll-Like Receptor 4
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Fluoxetine
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Protein Kinase C beta
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ACHE protein, human
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Acetylcholinesterase
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GTP-Binding Proteins