HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

ESeroS-GS modulates lipopolysaccharide-induced macrophage activation by impairing the assembly of TLR-4 complexes in lipid rafts.

Abstract
The binding of lipopolysaccharides (LPS) to macrophages results in inflammatory responses. In extreme cases it can lead to endotoxic shock, often resulting in death. A broad range of antioxidants, including tocopherols, can reduce LPS activity in vitro and in vivo. To elucidate the underlying mechanisms of their action, we investigated the effect of the sodium salt of γ-L-glutamyl-S-[2-[[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl]oxy]carbonyl]-3-[[2-(1H-indol-3-yl)ethyl]amino]-3-oxopropyl]-L-cysteinylglycine (ESeroS-GS), a novel α-tocopherol derivative, on LPS-induced inflammation in vitro and in vivo. ESeroS-GS reduced the transcription of TNF-α, IL-1β, IL-6 and iNOS genes in a dose-dependent manner in RAW264.7 macrophages, and inhibited the release of these inflammatory factors. In addition, ESeroS-GS inhibited LPS-induced mortality in a mouse sepsis model. Electrophoretic mobility shift assays (EMSA) and reporter gene assays revealed that ESeroS-GS down-regulated the transcriptional activity of NF-κB. By analyzing the partitioning of CD14 and Toll-like receptor 4 (TLR-4) in cell membrane microdomains, we found that ESeroS-GS attenuates the binding of LPS to RAW264.7 cells via interfering with the relocation of CD14 and TLR-4 to lipid rafts, blocking the activation of interleukin-1 receptor-associated kinase 1 (IRAK-1), and inhibiting the consequent phosphorylation of TAK1 and IKKα/β, which together account for the suppression of NF-κB activation. Taken together, our data suggest that ESeroS-GS can modulate LPS signaling in macrophages by impairing TLR-4 complex assembly via a lipid raft dependent mechanism. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
AuthorsWenjuan Duan, Juefei Zhou, Shen Zhang, Kai Zhao, Lijing Zhao, Kazumi Ogata, Takahiro Sakaue, Akitane Mori, Taotao Wei
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1813 Issue 5 Pg. 772-83 (May 2011) ISSN: 0006-3002 [Print] Netherlands
PMID21276822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright2011 Elsevier B.V. All rights reserved.
Chemical References
  • Benzopyrans
  • Cytokines
  • Indoles
  • Inflammation Mediators
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Multiprotein Complexes
  • NF-kappa B
  • Toll-Like Receptor 4
  • glutamyl-(2-(((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)carbonyl)-3-((2-(1H-indol-3-yl)ethyl)amino)-3-oxopropyl)-cysteinyl-glycine sodium salt
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Interleukin-1 Receptor-Associated Kinases
  • Irak1 protein, mouse
  • Chuk protein, mouse
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Fluorescein-5-isothiocyanate
Topics
  • Animals
  • Benzopyrans (chemistry, pharmacology)
  • Cell Line
  • Cytokines (biosynthesis)
  • Down-Regulation (drug effects)
  • Fluorescein-5-isothiocyanate (metabolism)
  • I-kappa B Kinase (metabolism)
  • Indoles (chemistry, pharmacology)
  • Inflammation Mediators (metabolism)
  • Interleukin-1 Receptor-Associated Kinases
  • Lipopolysaccharide Receptors (metabolism)
  • Lipopolysaccharides (pharmacology)
  • Longevity (drug effects)
  • MAP Kinase Kinase Kinases (metabolism)
  • Macrophage Activation (drug effects)
  • Macrophages (cytology, drug effects, enzymology)
  • Male
  • Membrane Microdomains (drug effects, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Multiprotein Complexes (metabolism)
  • NF-kappa B (metabolism)
  • Nitric Oxide (biosynthesis)
  • Nitric Oxide Synthase Type II (metabolism)
  • Phosphorylation (drug effects)
  • Sepsis (metabolism, pathology)
  • Toll-Like Receptor 4 (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: