title: 5,6,7-trimethoxyflavone suppresses pro-inflammatory mediators in lipopolysaccharide-induced RAW 264.7 macrophages and protects mice from lethal endotoxin shock.
abstract: 5,6,7-Trimethoxyflavone (TMF), methylations of the hydroxyl groups of oroxylin A or baicalein, was found to significantly inhibit the productions of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. However, no report has been issued on the anti-inflammatory potential of TMF and the underlying molecular mechanism. In the present study, we investigated the anti-inflammatory effects of TMF in LPS-induced RAW 264.7 macrophages and LPS-induced septic shock in mice. TMF dose-dependently inhibits iNOS and COX-2 at the protein, mRNA, and promoter binding levels and that these inhibitions cause attendant decreases in the productions of NO and PGE2. TMF inhibits the productions and mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 induced by LPS. Furthermore, TMF suppress the transcriptional activity of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), and nuclear translocations of NF-κB, AP-1, and signal transducer and activator of transcription 1/3 (STAT1/3). Pretreatment with TMF increase the survival rate of mice with LPS-induced endotoxemia and reduced the serum levels of cytokines. Taken together, these findings suggest that TMF down-regulates the expressions of the pro-inflammatory iNOS, COX-2, TNF-α, IL-1β, and IL-6 genes in macrophages by interfering with the activation of NF-κB, AP-1, and STAT1/3.
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Republic of Korea; Department of Biomedical Science, College of Medical Science, Kyung Hee University, 1 Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Republic of Korea.
authors.forename: Hong-Kun
authors.initials: HK
authors.lastname: Rim
authors.forename: Chang Hyeon
authors.initials: CH
authors.lastname: Yun
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.forename: Young-Wuk
authors.initials: YW
authors.lastname: Cho
authors.forename: Dae Sik
authors.initials: DS
authors.lastname: Jang
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Ryu
authors.forename: Haeil
authors.initials: H
authors.lastname: Park
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000188:drug therapy / Q000401:mortality; D005419:Flavonoids / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C107364:5,6,7-trimethoxyflavone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D005419:Flavonoids; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: 5,6,7-Trimethoxyflavone; Cyclooxygenase-2; Inducible nitric oxide synthase; Inflammation; Nuclear factor-kappa B; Sepsis