Hirsutenone inhibits lipopolysaccharide-activated NF-kappaB-induced inflammatory mediator production by suppressing Toll-like receptor 4 and ERK activation

• Published in: International immunopharmacology Vol. 10; no. 4; pp. 520 - 525
• Main Authors: Lee, Chung Soo, Jang, Eun-Ra, Kim, Yun Jeong, Lee, Min Sung, Seo, Seong Jun, Lee, Min Won
• Format: Journal Article
• Language: English
• Published: Netherlands 01.04.2010
• Subjects: Alnus - chemistry; Catechols - pharmacology; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cells, Cultured; Chemokine CCL17 - biosynthesis; Cytosol - drug effects; Cytosol - metabolism; Dermatitis - drug therapy; Dermatitis - pathology; Diarylheptanoids - pharmacology; Enzyme Activation - drug effects; Enzyme-Linked Immunosorbent Assay; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Humans; Inflammation Mediators - metabolism; Interleukin-18 - biosynthesis; Interleukin-1beta - biosynthesis; Keratinocytes - drug effects; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; NF-kappa B - drug effects; Skin - pathology; Toll-Like Receptor 4 - antagonists & inhibitors
• ISSN: 1878-1705
• DOI: 10.1016/j.intimp.2010.01.015

Microbial products, including lipopolysaccharide, may be involved in the pathogenesis of skin diseases such as atopic dermatitis. Diarylheptanoids such as oregonin and hirsutenone have been shown to have an anti-inflammatory effect. We investigated the effect of hirsutenone on lipopolysaccharide-induced inflammatory mediator production in keratinocytes in relation to the Toll-like receptor 4-mediated activation of the extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-kappaB pathways. Hirsutenone, dexamethasone, ERK inhibitor or Bay 11-7085 (an inhibitor of NF-kappaB activation) reduced the lipopolysaccharide-induced production of cytokines IL-1beta and IL-8, and the chemokine CCL17. Hirsutenone, ERK inhibitor or Bay 11-7085 also prevented the lipopolysaccharide-induced expression of Toll-like receptor 4, the phosphorylation of inhibitory kappaB-alpha, the activation of NF-kappaB and the expression of ERK. The results show that hirsutenone may reduce the lipopolysaccharide-stimulated production of inflammatory mediators in keratinocytes by suppressing the Toll-like receptor 4 expression-mediated NF-kappaB activation that is regulated by the ERK pathway. These findings suggest that hirsutenone may exert a preventive effect against microbial endotoxin lipopolysaccharide-induced inflammatory skin diseases through inhibition of ERK pathway-mediated NF-kappaB activation.