title: Suppression of inflammatory responses by handelin, a guaianolide dimer from Chrysanthemum boreale, via downregulation of NF-κB signaling and pro-inflammatory cytokine production.
abstract: The anti-inflammatory activity of handelin (1), a guaianolide dimer from Chrysanthemum boreale flowers, was evaluated in vivo, and the effects on mediators nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) and the nuclear factor-κB (NF-κB) and ERK/JNK signaling pathways were investigated in vitro. Compound 1 inhibited lipopolysaccharide (LPS)-induced production of NO and PGE2 in cultured mouse macrophage RAW 264.7 cells. The suppression of NO and PGE2 production by 1 was correlated with the downregulation of mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Compound 1 also suppressed the induction of pro-inflammatory cytokines TNF-α and IL-1β in LPS-stimulated RAW 264.7 cells. To further clarify the transcriptional regulatory pathway in the expression of iNOS and COX-2 by 1, the role of NF-κB was determined in RAW 264.7 cells. Compound 1 inhibits the binding activity of NF-κB into the nuclear proteins. The transcriptional activity of NF-κB stimulated with LPS was also suppressed by 1, which coincided with the inhibition of IκB degradation. Compound 1 also suppressed the activation of mitogen-activated protein kinases, including ERK and JNK signaling. In addition, the LPS-stimulated upregulation of miRNA-155 expression was suppressed by 1. The oral administration of 1 inhibited acute inflammation in carrageenan-induced paw and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema models. The serum level of IL-1β was also inhibited by 1 in a carrageenan-induced paw edema model. These findings suggest that the suppression of NF-κB activation and pro-inflammatory cytokine production may be a plausible mechanism of action for the anti-inflammatory activity of handelin.
authors.affiliation: College of Pharmacy, Natural Products Research Institute, Seoul National University , Seoul 151-742, Korea.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Pyee
authors.forename: Hwa-Jin
authors.initials: HJ
authors.lastname: Chung
authors.forename: Tae Jun
authors.initials: TJ
authors.lastname: Choi
authors.forename: Hyen Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.forename: Ju Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Sam Sik
authors.initials: SS
authors.lastname: Kang
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D031202:Chrysanthemum / Q000737:chemistry*; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D023421:Models, Animal; D015394:Molecular Structure; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D008517:Phytotherapy; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; C053046:handelin; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone