title: Aesculin inhibits matrix metalloproteinase-9 expression via p38 mitogen activated protein kinase and activator protein 1 in lipopolysachride-induced RAW264.7 cells.
abstract: Expression of matrix metalloproteinase 9 (MMP-9) may contribute to inflammatory conditions such as arthritis, hepatitis, atherosclerosis, and pulmonary fibrosis, which involves the destruction of the extracellular matrix (ECM). Macrophages stimulated with lipopolysaccharide (LPS) express MMP-9 through the nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1) signaling pathways. Aesculin, a 6,7-dihydroxycoumarin-6-O-beta-glucopyranoside, has been highlighted for its anti-hepatotoxic, hypouricemic, antioxidative, photo-protective, and anti-apoptotic properties. In this study, we investigated the effects of aesculin on LPS-stimulated MMP-9 production and its regulatory mechanism by using murine macrophage RAW264.7 cells. Aesculin did not trigger any significant cytotoxic effect on RAW264.7 cells at concentration up to 150 μM. Secretion and expression levels of MMP-9, which were highly elevated by LPS treatment, were reduced by the addition of aesculin in a dose-dependent manner. However, gelatinolytic activity of MMP-9 was not reduced by aesculin. Luciferase activity assays and electrophoretic mobility shift assays using RAW264.7 cells showed that the inhibition of MMP-9 expression by aesculin was mediated by AP-1 rather than NF-κB. In addition, aesculin inhibited phosphorylation of p38 MAPK and subsequent activation of c-fos, a component of AP-1 transcription factor, but not JNK, ERK1/2, and c-jun. These findings suggest that aesculin is a potent drug candidate that protects against the inflammatory destruction of ECM.
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam, 626-870, Republic of Korea.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chung
authors.forename: Jai-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Han-Sol
authors.initials: HS
authors.lastname: Jeong
authors.forename: Myungsoo
authors.initials: M
authors.lastname: Joo
authors.forename: Jaeho
authors.initials: J
authors.lastname: Cha
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: Ki-Tae
authors.initials: KT
authors.lastname: Ha
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004929:Esculin / Q000494:pharmacology*; D008070:Lipopolysaccharides; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D004929:Esculin; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse