title: Ethyl caffeate suppresses NF-kappaB activation and its downstream inflammatory mediators, iNOS, COX-2, and PGE2 in vitro or in mouse skin.
abstract: Ethyl caffeate, a natural phenolic compound, was isolated from Bidens pilosa, a medicinal plant popularly used for treating certain inflammatory syndromes. The purpose of this study was to investigate the structural activity, and the anti-inflammatory functions and mechanism(s) of ethyl caffeate. Ethyl caffeate was found to markedly suppress the lipopolysaccharide (LPS)-induced nitric oxide (NO) production (IC(50) = 5.5 microg ml(-1)), mRNA and protein expressions of inducible nitric oxide synthase (iNOS), and prostaglandin E(2) (PGE(2)) production in RAW 264.7 macrophages. Transient gene expression assays using human cox-2 promoter construct revealed that ethyl caffeate exerted an inhibitory effect on cox-2 transcriptional activity in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 cells. Immunohistochemical studies of mouse skin demonstrated that TPA-induced COX-2 expression was significantly inhibited by ethyl caffeate with a superior effect to that of celecoxib, a nonsteroidal anti-inflammatory drug. The phosphorylation and degradation of inhibitor kappaB (IkappaB) and the translocation of nuclear transcription factor-kappaB (NF-kappaB) into the nucleus, as well as the activation of mitogen-activated protein kinases (MAPKs) induced by LPS in macrophages, were not affected by ethyl caffeate. Ethyl caffeate, however, could inhibit NF-kappaB activation by impairing the binding of NF-kappaB to its cis-acting element. These results suggest that ethyl caffeate suppresses iNOS and COX-2 expressions partly through the inhibition of the NF-kappaB.DNA complex formation. Structure-activity relationship analyses suggested that the catechol moiety and alpha,beta-unsaturated ester group in ethyl caffeate are important and essential structural features for preventing NF-kappaB.DNA complex formation. This study provides an insight into the probable mechanism(s) underlying the anti-inflammatory and therapeutic properties of ethyl caffeate.
authors.affiliation: 1Institute of BioAgricultural Sciences, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Chiang
authors.forename: Chiu-Ping
authors.initials: CP
authors.lastname: Lo
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Chen
authors.forename: Sheng-Yang
authors.initials: SY
authors.lastname: Wang
authors.forename: Ning-Sun
authors.initials: NS
authors.lastname: Yang
authors.forename: Yueh-Hsiung
authors.initials: YH
authors.lastname: Kuo
authors.forename: Lie-Fen
authors.initials: LF
authors.lastname: Shyur
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D031176:Bidens; D002109:Caffeic Acids / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005591:Chemical Fractionation; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004365:Drugs, Chinese Herbal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate
chemical_list: D000893:Anti-Inflammatory Agents; D002109:Caffeic Acids; D016861:Cyclooxygenase Inhibitors; D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; C442780:plant extract, Bidens pilosa; D009569:Nitric Oxide; C032773:ethyl caffeate; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate