Abstract
Non-receptor protein tyrosine kinases (NRPTKs)-dependent inflammatory signal transduction cascades play key roles in immunoregulation. However, drug intervention through NRPTKs-involved immunoregulation mechanism in microglia (the major immune cells of the central nervous system) has not been widely investigated. A main aim of the present study is to elucidate the contribution of two major NRPTKs (Syk and Jak2) in neuroinflammation suppression by a bioactive sesquiterpene dimmer (DSF-27). We found that LPS-stimulated BV-2 cells activated Syk and further initiated Akt/NF-κB inflammatory pathway. This Syk-dependent Akt/NF-κB inflammatory pathway can be effectively ameliorated by DSF-27. Moreover, Jak2 was activated by LPS, which was followed by transcriptional factor Stat3 activation. The Jak2/Stat3 signal was suppressed by DSF-27 through inhibition of Jak2 and Stat3 phosphorylation, promotion of Jak/Stat3 inhibitory factors PIAS3 expression, and down-regulation of ERK and p38 MAPK phosphorylation. Furthermore, DSF-27 protected cortical and mesencephalic dopaminergic neurons against neuroinflammatory injury. Taken together, our findings indicate NRPTK signaling pathways including Syk/NF-κB and Jak2/Stat3 cascades are potential anti-neuroinflammatory targets in microglia, and may also set the basis for the use of sesquiterpene dimmer as a therapeutic approach for neuroinflammation via interruption of these pathways.
Keywords:
Microglia; Neuroinflammation; Non-receptor tyrosine kinase; Sesquiterpene dimmer.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology*
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Artemisia / chemistry
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Cell Line
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Coculture Techniques
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Dopaminergic Neurons / drug effects
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Dopaminergic Neurons / enzymology
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Dopaminergic Neurons / immunology
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Dose-Response Relationship, Drug
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Inflammation / enzymology
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / prevention & control*
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Inflammation Mediators / metabolism*
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Janus Kinase 2 / antagonists & inhibitors*
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Janus Kinase 2 / metabolism
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Lipopolysaccharides / pharmacology
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Mice
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Microglia / drug effects*
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Microglia / enzymology
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Microglia / immunology
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Models, Molecular
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Molecular Docking Simulation
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Molecular Structure
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NF-kappa B / metabolism
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Phosphorylation
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Protein Inhibitors of Activated STAT / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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STAT3 Transcription Factor
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Sesquiterpenes / chemistry
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Sesquiterpenes / pharmacology*
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Signal Transduction / drug effects*
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Syk Kinase
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Time Factors
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Transfection
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anti-Inflammatory Agents
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DSF-27 compound
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Inflammation Mediators
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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NF-kappa B
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Pias3 protein, mouse
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Protein Inhibitors of Activated STAT
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STAT3 Transcription Factor
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Sesquiterpenes
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Stat3 protein, mouse
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Protein-Tyrosine Kinases
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Jak2 protein, mouse
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Janus Kinase 2
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Syk Kinase
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Syk protein, mouse
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases