Lindenane‐Type Sesquiterpene Dimers Mitigate Lipopolysaccharide‐Induced Inflammation by Inhibiting Toll‐Like Receptor Signaling

Abstract

AbstractToll‐like receptors (TLRs) recognize pathogen‐associated molecular patterns and trigger an inflammatory response via the myeloid differential factor 88 (MyD88)‐dependent and toll‐interleukin‐1 receptor domain‐containing adapter‐inducing interferon‐β (TRIF)‐dependent pathways. Lindenane type sesquiterpene dimers (LSDs) are characteristic metabolites of plants belonging to the genus Sarcandra (Chloranthaceae). The aim of this study was to evaluate the potential anti‐inflammatory effects of the LSDs shizukaol D (1) and sarcandrolide E (2) on lipopolysaccharides (LPS)‐stimulated RAW264.7 macrophages in vitro, and explore the underlying mechanisms. Both LSDs neutralized the LPS‐induced morphological changes and production of nitric oxide (NO), as determined by CCK‐8 assay and Griess assay, respectively. Furthermore, shizukaol D (1) and sarcandrolide E (2) downregulated interferon β (IFNβ), tumor necrosis factor α (TNFα) and interleukin‐1β (IL‐1β) mRNA levels as measured by reverse transcription polymerase chain reaction (RT‐PCR), and inhibited the phosphorylation of nuclear factor kappa B p65 (p65), nuclear factor kappa‐Bα (IκBα), Jun N‐terminal kinase (JNK), extracellular regulated kinase (ERK), mitogen‐activated protein kinase p38 (p38), MyD88, IL‐1RI‐associated protein kinase 1 (IRAK1), and transforming growth factor‐β‐activated kinase 1 (TAK1) proteins in the Western blotting assay. In conclusion, LSDs can alleviate the inflammatory response by inhibiting the TLR/MyD88 signalling pathway.