Compound FLZ inhibits lipopolysaccharide-induced inflammatory effects via down-regulation of the TAK-IKK and TAK-JNK/p38MAPK pathways in RAW264.7 macrophages.
Acta Pharmacol Sin
; 30(2): 209-18, 2009 Feb.
Article
em En
| MEDLINE
| ID: mdl-19169268
ABSTRACT
AIM:
The aim of this study was to investigate the effect of the squamosamide derivative FLZ (N-2-(4-hydroxy-phenyl)-ethyl-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) on lipopolysaccharide (LPS)-induced inflammatory mediator production and the underlying mechanism in RAW264.7 macrophages.METHODS:
RAW264.7 cells were preincubated with non-toxic concentrations of compound FLZ (1, 5, and 10 micromol/L) for 30 min and then stimulated with 10 microg/L LPS. The production of nitric oxide (NO), the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), and the activation of nuclear factor kappa-B (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways were examined.RESULTS:
FLZ significantly inhibited the LPS-induced production of NO, as well as the expression of iNOS and COX-2 at both the RNA and the protein levels in RAW264.7 cells. The LPS-induced increase in the DNA binding activity of NF-kappaB and activator protein 1 (AP-1), the nuclear translocation of NF-kappaB p65, the degradation of the inhibitory kappaBalpha protein (IkappaBalpha) and the phosphorylation of IkappaBalpha, IkappaB kinase (IKK) alpha/beta, c-Jun NH(2)-terminal kinase (JNK) and p38 MAPKs were all suppressed by FLZ. However, the phosphorylation of extracellular signal-regulated kinase (ERK) was not affected. Further study revealed that FLZ inhibited the phosphorylation of transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1), which is an upstream signaling molecule required for IKKalpha/beta, JNK and p38 activation.CONCLUSION:
FLZ inhibited the LPS-induced production of inflammatory mediators at least partly through the downregulation of the TAK-IKK and TAK-JNK/p38MAPK pathways.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenóis
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Lipopolissacarídeos
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MAP Quinase Quinase Quinases
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Sistema de Sinalização das MAP Quinases
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Benzenoacetamidas
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Proteínas Quinases JNK Ativadas por Mitógeno
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Proteínas Quinases p38 Ativadas por Mitógeno
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Quinase I-kappa B
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Macrófagos
Limite:
Animals
Idioma:
En
Revista:
Acta Pharmacol Sin
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
China