Abstract
We investigated the interaction between proinflammatory and inflammatory responses caused by Staphylococcus aureus-derived lipoteichoic acid (LTA) in primary cultured microglial cells and BV-2 microglia. LTA induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels increase in a concentration- and time-dependent manner. Meanwhile, LTA also increased nitric oxide (NO) and PGE2 production in microglia. Administration of TLR2 antagonist effectively inhibited LTA-induced NO, iNOS, and COX-2 expression. Moreover, treatment of cells with LTA caused a time-dependent activation of ERK, p38, JNK, as well as AKT. We also found that LTA-induced iNOS and COX-2 up-regulation were attenuated by p38, JNK, and PI3-kinase inhibitors. On the other hand, LTA-enhanced HO-1 expression was attenuated by p38 and PI3-kinase inhibitors. Treatment of cells with NF-κB and AP-1 inhibitors antagonized LTA-induced iNOS and COX-2 expression. However, only NF-κB inhibitors reduced LTA-induced HO-1 expression in microglia. Furthermore, stimulation of cells with LTA also activated IκBα phosphorylation, p65 phosphorylation at Ser⁵³⁶, and c-Jun phosphorylation. Moreover, LTA-induced increases of κB-DNA and AP-1-DNA binding activity were inhibited by p38, JNK, and PI3-kinase inhibitors. HO-1 activator CoPP IX dramatically reversed LTA-induced iNOS expression. Our results provided mechanisms linking LTA and inflammation/anti-inflammation, and indicated that LTA plays a regulatory role in microglia activation.
Copyright © 2013 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 / pharmacology
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Cells, Cultured
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Cyclooxygenase 2 / metabolism
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Dinoprostone / metabolism
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Dose-Response Relationship, Drug
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Enzyme Activation
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Heme Oxygenase (Decyclizing) / metabolism
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Inflammation / immunology*
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Inflammation / metabolism
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Inflammation / prevention & control
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Inflammation Mediators / metabolism
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Lipopolysaccharides / isolation & purification
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Lipopolysaccharides / pharmacology*
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Microglia / drug effects*
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Microglia / immunology
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Microglia / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type II / metabolism
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Primary Cell Culture
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Staphylococcus aureus / metabolism*
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Teichoic Acids / isolation & purification
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Teichoic Acids / pharmacology*
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Time Factors
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Toll-Like Receptor 2 / antagonists & inhibitors
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Toll-Like Receptor 2 / metabolism
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Transcription Factor AP-1 / metabolism
Substances
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Anti-Inflammatory Agents
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Inflammation Mediators
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Lipopolysaccharides
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Teichoic Acids
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Tlr2 protein, rat
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Toll-Like Receptor 2
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Transcription Factor AP-1
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Nitric Oxide
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lipoteichoic acid
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Nitric Oxide Synthase Type II
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Nos2 protein, rat
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Heme Oxygenase (Decyclizing)
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Hmox1 protein, rat
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Cyclooxygenase 2
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Ptgs2 protein, rat
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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Dinoprostone