title: Heme oxygenase-1-mediated anti-inflammatory effects of tussilagonone on macrophages and 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation in mice.
abstract: The dried flower buds of Tussilago farfara L. have been used in traditional medicine, mainly as an antitussive in the treatment of cough and other respiratory problems. In the present study, we investigated the anti-inflammatory signaling pathway via the upregulation of heme oxygenase-1 (HO-1) in response to tussilagonone (TGN), a sesquiterpene compound isolated from T. farfara. TGN induced HO-1 expression and nuclear factor-E2-related factor 2 (Nrf2) activation in RAW 264.7 cells. Nuclear translocation of Nrf2 by TGN also increased in a time- and dose-dependent manner, indicating that TGN induced HO-1 via the Nrf2 pathway. Consistent with the notion that HO-1 has anti-inflammatory properties, TGN suppressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and reduced the mRNA expression of proinflammatory cytokines, as well as nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. TGN inhibited the phosphorylation and degradation of inhibitory κB-α (IκB-α) and the nuclear translocation of nuclear factor (NF)-κB. However, a specific inhibitor of HO-1 reversed the TGN-mediated suppression of NO production and knockdown of HO-1 by small interfering RNA abrogated inhibitory effects of TGN on iNOS and COX-2 protein expression and NF-κB nuclear translocation. Furthermore, TGN reduced iNOS and COX-2 expression in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation mouse model. Taken together, these findings suggest an important role for TGN-induced HO-1 activation in regulating inflammatory responses. Moreover, TGN is a potent therapeutic candidate for targeting the crosstalk between Nrf2/HO-1 and the NF-κB signaling pathway in the prevention or treatment of inflammation-associated diseases.
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Joohee
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences (Ewha Global Top 5 Program), Seoul 120-750, South Korea.
authors.forename: Unwoo
authors.initials: U
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences (Ewha Global Top 5 Program), Seoul 120-750, South Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Seo
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea. Electronic address: kims@snu.ac.kr.
authors.forename: Yeong Shik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy*; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010703:Phorbol Esters / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D012717:Sesquiterpenes / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D031207:Tussilago / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D010703:Phorbol Esters; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; C000600213:12-O-undecadienoylphorbol-13-acetate; C054337:tussilagone; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2
keywords: Anti-inflammatory; Heme oxygenase-1; NF-κB; Nrf2; Tussilago farfara; Tussilagonone