Celastrol blocks binding of lipopolysaccharides to a Toll-like receptor4/myeloid differentiation factor2 complex in a thiol-dependent manner

摘要: Abstract Ethnopharmacological relevance Tripterygium wilfordii (lei gong teng; Thunder of God Vine), which belongs to the Celastraceae family, has long been used in traditional Chinese medicine treat inflammation and rheumatoid arthritis. Celastrol is a bioactive compound isolated from T. wilfordii. Aim study We investigated whether celastrol suppressed binding lipopolysaccharides (LPS) myeloid differentiation factor 2 (MD2), thereby downregulating Toll-like receptor4 (TLR4) activation mouse primary macrophages. Materials methods Cytokine expression was determined by polymerase chain reaction analysis enzyme-linked immunosorbent assay bone marrow-derived macrophages (BMDMs). The kinase activity tank-binding 1 (TBK1) examined luciferase reporter an vitro assay. LPS MD2 confocal microscopy analysis. Results reduced LPS-induced inflammatory cytokines, such as tumor necrosis (TNF)-α, interleukin (IL)-6, IL-12, IL-1β, at both mRNA protein levels BMDMs. MD2, shown assay, whereas it did not inhibit TBK1. In addition, co-localization with BMDMs blocked celastrol. inhibitory effects on were reversed thiol donors (N-acetyl- L -cysteine dithiothreitol), suggesting that reactivity contributes its TLR4 Conclusion Our results demonstrate suppresses through inhibition TLR4/MD2 complex. These provide novel mechanism action anti-inflammatory .