Echinocystic acid ameliorates lung inflammation in mice and alveolar macrophages by inhibiting the binding of LPS to TLR4 in NF-κB and MAPK pathways

Eun-Ha Joh, Wan Gu, Dong-Hyun Kim
Biochemical Pharmacology 2012 August 1, 84 (3): 331-40
Orally administered lancemaside A, which is isolated from Codonopsis lanceolata (family Campanulaceae), showed anti-colitic effect in mice. However, its metabolite echinocystic acid was absorbed into the blood. Therefore, its anti-inflammatory effects were investigated in lipopolysaccharide (LPS)-stimulated alveolar macrophages in vitro and acute lung injury in vivo. Alveolar macrophages from mice were stimulated with LPS and were treated with echinocystic acid. Acute lung injury was induced by intratracheal administration of LPS in mice. Mice were treated with echinocystic acid or dexamethasone. Echinocystic acid potently suppressed the production of the pro-inflammatory cytokines, TNF-α and IL-1β, as well as of the activations of NF-κB and MAPKS, in LPS-stimulated alveolar macrophages. Echinocystic acid also down-regulated the production of inflammatory markers, which included inducible nitric oxide synthase and cyclooxygenase-2, as well as the inflammatory mediators, nitric oxide and prostaglandin E(2), in LPS-stimulated alveolar macrophages. Echinocystic acid also inhibited the activation of IL-1 receptor-associated kinases, and the activation of mitogen-activated protein kinases in LPS-stimulated alveolar macrophages. Furthermore, echinocystic acid potently inhibited the interaction between LPS and TLR4 in alveolar macrophages transfected with or without MyD88 siRNA, although it did not inhibit the binding in the macrophages transfected with TLR4 siRNA. Echinocystic acid suppressed LPS-induced acute lung inflammation in mice, as well as the expression of pro-inflammatory cytokines, such as IL-1β and TNF-α, and their transcription factor, NF-κB. On the basis of these findings, echinocystic acid, a metabolite of lancemaside A, may express anti-inflammatory effects by inhibiting the binding of LPS to TLR4 on macrophages.

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