title: Sesquiterpene lactone parthenolide attenuates production of inflammatory mediators by suppressing the Toll-like receptor-4-mediated activation of the Akt, mTOR, and NF-κB 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-κB 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-κB 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-1β and PGE2, 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-κB 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-κB 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.
authors.affiliation: Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul, 156-756, South Korea.
authors.forename: Yoon Jeong
authors.initials: YJ
authors.lastname: Nam
authors.forename: Da Hee
authors.initials: DH
authors.lastname: Lee
authors.forename: Min Sung
authors.initials: MS
authors.lastname: Lee
authors.forename: Chung Soo
authors.initials: CS
authors.lastname: Lee
mesh_terms: D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D051197:Toll-Like Receptor 4; C002669:parthenolide; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases