Sesquiterpene lactone parthenolide attenuates production of inflammatory mediators by suppressing the Toll-like receptor-4-mediated activation of the Akt, mTOR, and NF-kappa B pathways

Abstract

Microbial product lipopolysaccharide has been shown to be involved in the pathogenesis of inflammatory skin diseases. Parthenolide present in extracts of the herb feverfew has demonstrated an anti-inflammatory effect. However, the effect of parthenolide on the Akt/mTOR and NF-kappa B pathway activation-induced productions of inflammatory mediators in keratinocytes has not been studied. Using human keratinocytes, we investigated the effect of parthenolide on the inflammatory mediator production in relation to the Toll-like receptor-4-mediated-Akt/mTOR and NF-kappa B pathways, which regulate the transcription genes involved in immune and inflammatory responses. Parthenolide, Akt inhibitor, Bay 11-7085, and N-acetylcysteine each attenuated the lipopolysaccharide-induced production of IL-1 beta and PGE(2), increase in the levels of cyclooxygenase, formation of reactive oxygen species, increase in the levels of Toll-like receptor-4, and activation of the Akt/mTOR and NF-kappa B in keratinocytes. The results show that parthenolide appears to attenuate the lipopolysaccharide-stimulated production of inflammatory mediators in keratinocytes by suppressing the Toll-like receptor-4-mediated activation of the Akt, mTOR, and NF-kappa B pathways. The activation of signaling transduction pathways appear to be regulated by reactive oxygen species. Parthenolide appears to attenuate the microbial product-mediated inflammatory skin diseases.