title: 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.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Duan
authors.forename: Juefei
authors.initials: J
authors.lastname: Zhou
authors.forename: Shen
authors.initials: S
authors.lastname: Zhang
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.forename: Lijing
authors.initials: L
authors.lastname: Zhao
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ogata
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sakaue
authors.forename: Akitane
authors.initials: A
authors.lastname: Mori
authors.forename: Taotao
authors.initials: T
authors.lastname: Wei
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018805:Sepsis / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D001578:Benzopyrans; D016207:Cytokines; D016650:Fluorescein-5-isothiocyanate; D051550:I-kappa B Kinase; D007211:Indoles; D018836:Inflammation Mediators; D053592:Interleukin-1 Receptor-Associated Kinases; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051197:Toll-Like Receptor 4; D000099151:MAP Kinase Kinase Kinase 7; C475739: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; C507769:Irak1 protein, mouse; C496564:Chuk protein, mouse