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.