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A Novel Chromone Derivative with Anti-Inflammatory Property via Inhibition of ROS-Dependent Activation of TRAF6-ASK1-p38 Pathway
- Source :
- PLoS ONE, Vol 7, Iss 8, p e37168 (2012), PLoS ONE
- Publication Year :
- 2012
- Publisher :
- Public Library of Science (PLoS), 2012.
-
Abstract
- The p38 MAPK signaling pathway plays a pivotal role in inflammation. Targeting p38 MAPK may be a potential strategy for the treatment of inflammatory diseases. In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1β and IL-6, decreased the levels of iNOS, IL-1β and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK. Moreover, DCO-6 specifically inhibited TLR4-dependent p38 activation without directly inhibiting its kinase activity. LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex. Administering DCO-6 significantly protected mice from LPS-induced septic shock in parallel with the inhibition of p38 activation and ROS production. Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway. Blockade of the upstream events required for p38 MAPK action by DCO-6 may provide a new therapeutic option in the treatment of inflammatory diseases.
- Subjects :
- Lipopolysaccharides
Male
MAPK/ERK pathway
Critical Care and Emergency Medicine
Lipopolysaccharide
Interleukin-1beta
Anti-Inflammatory Agents
Gene Expression
lcsh:Medicine
Signal transduction
p38 Mitogen-Activated Protein Kinases
Mice
chemistry.chemical_compound
Molecular cell biology
ASK1
lcsh:Science
Cells, Cultured
Mice, Inbred BALB C
Multidisciplinary
Molecular Structure
Reverse Transcriptase Polymerase Chain Reaction
Signaling cascades
Signaling in Selected Disciplines
Shock, Septic
Cell biology
Medicine
Tumor necrosis factor alpha
medicine.symptom
Research Article
MAPK signaling cascades
Cell Survival
p38 mitogen-activated protein kinases
Immunology
Immunoblotting
Inflammation
Biology
Immunological Signaling
MAP Kinase Kinase Kinase 5
Cell Line
Sepsis
Cell Line, Tumor
medicine
Animals
Kinase activity
TNF Receptor-Associated Factor 6
Tumor Necrosis Factor-alpha
Macrophages
lcsh:R
Immunity
Molecular biology
chemistry
Chromones
Macrophages, Peritoneal
lcsh:Q
Reactive Oxygen Species
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....e769b2eb329bd175cd7c8d31a0a9f703