title: Alantolactone suppresses inducible nitric oxide synthase and cyclooxygenase-2 expression by down-regulating NF-κB, MAPK and AP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7 cells.
abstract: Several sesquiterpene lactones are the active components of several medicinal plants and have been demonstrated to perform various pharmacological functions. In this study, we investigated the anti-inflammatory effects of alantolactone, a sesquiterpene lactone isolated from the root of Aucklandia lappa, in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and peritoneal macrophages. Alantolactone inhibited inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) protein and mRNA transcription, as well as the downstream products, nitric oxide (NO), prostaglandin E(2) (PGE(2)) and tumor necrosis factor-α (TNF-α). Investigation of the effects on nuclear factor κB (NF-κB) signaling showed that alantolactone inhibits the phosphorylation of inhibitory κB (IκB)-α and IκB kinase (IKK) and the subsequent translocation of the p65 and p50 NF-κB subunits to the nucleus. Moreover, inhibition of mitogen-activated protein kinases (MAPKs), including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 MAPK, and activator protein-1 (AP-1) was also observed. A further study indicated that alantolactone attenuated the phosphorylation of Akt and inhibited the expression of MyD88 and Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP), an upstream signaling molecule required for IKK and MAPKs activation. Taken together, these results suggest that alantolactone exerts its anti-inflammatory effect in LPS-stimulated RAW 264.7 cells by suppressing NF-κB activation and MAPKs phophorylation via downregulation of the MyD88 signaling pathway. Thus, alantolactone may provide a useful therapeutic approach for inflammation-associated diseases.
authors.affiliation: Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jaemoo
authors.initials: J
authors.lastname: Chun
authors.forename: Ran Joo
authors.initials: RJ
authors.lastname: Choi
authors.forename: Salman
authors.initials: S
authors.lastname: Khan
authors.forename: Dong-Sung
authors.initials: DS
authors.lastname: Lee
authors.forename: Youn-Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Nam
authors.forename: Dong-Ung
authors.initials: DU
authors.lastname: Lee
authors.forename: Yeong Shik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D045787:Sesquiterpenes, Eudesmane / Q000737:chemistry / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007783:Lactones; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D045787:Sesquiterpenes, Eudesmane; D018808:Transcription Factor AP-1; D019001:Nitric Oxide Synthase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020929:Mitogen-Activated Protein Kinase Kinases; C004363:alantolactone