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5-Methoxyl Aesculetin Abrogates Lipopolysaccharide-Induced Inflammation by Suppressing MAPK and AP-1 Pathways in RAW 264.7 Cells.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2016 Mar 01; Vol. 17 (3), pp. 315. Date of Electronic Publication: 2016 Mar 01. - Publication Year :
- 2016
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Abstract
- For the first time, a pale amorphous coumarin derivative, 5-methoxyl aesculetin (MOA), was isolated from the dried bark of Fraxinus rhynchophylla Hance (Oleaceae). MOA modulates cytokine expression in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages, but the precise mechanisms are still not fully understood. We determined the effects of MOA on the production of inflammatory mediators and pro-inflammatory cytokines in the LPS-induced inflammatory responses of RAW 264.7 macrophages. MOA significantly inhibited the LPS-induced production of nitric oxide (NO), prostaglandin E₂ (PGE₂), tumor necrosis factor-α (TNF-α), interleukin-6, and interleukin-1β. It also effectively attenuated inducible nitric oxide (NO) synthase, cyclooxygenase-2, and TNF-α mRNA expression and significantly decreased the levels of intracellular reactive oxygen species. It inhibited phosphorylation of the extracellular signal-regulated kinase (ERK1/2), thus blocking nuclear translocation of activation protein (AP)-1. In a molecular docking study, MOA was shown to target the binding site of ERK via the formation of three hydrogen bonds with two residues of the kinase, which is sufficient for the inhibition of ERK. These results suggest that the anti-inflammatory effects of MOA in RAW 264.7 macrophages derive from its ability to block both the activation of mitogen-activated protein kinases (MAPKs) and one of their downstream transcription factors, activator protein-1 (AP-1). Our observations support the need for further research into MOA as a promising therapeutic agent in inflammatory diseases.
- Subjects :
- Animals
Cell Line
Cyclooxygenase 2 genetics
Cyclooxygenase 2 metabolism
Dinoprostone metabolism
Interleukins genetics
Interleukins metabolism
Lipopolysaccharides toxicity
Macrophages metabolism
Mice
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Nitric Oxide metabolism
Tumor Necrosis Factor-alpha genetics
Tumor Necrosis Factor-alpha metabolism
Antioxidants pharmacology
MAP Kinase Signaling System
Macrophages drug effects
Transcription Factor AP-1 metabolism
Umbelliferones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 17
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 26938526
- Full Text :
- https://doi.org/10.3390/ijms17030315