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《中国药理学报：英文版》
>Compound FLZ inhibits lipopolysaccharide-induced inflammatory effects via down-regulation of the TAK-IKK and TAK-JNK/ p38MAPK pathways in RAW264.7 macrophages
Compound FLZ inhibits lipopolysaccharide-induced inflammatory effects via down-regulation of the TAK-IKK and TAK-JNK/ p38MAPK pathways in RAW264.7 macrophages
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 inflam-matory 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 μmol/L) for 30 min and then stimulated with 10 μg/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-κB) 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-κBand activator protein I (AP-1),the nuclear translocation of NF-κB p65,the degradation of the inhibitory κBα protein (IκBα)and the phosphorylation of IκBα,IκB kinase (IKK) α/β,c-Jun NH2-terminal kinase (JNK) and p38 MAPKs were all sup-pressed 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-β (TGF-β)-activated kinase 1 (TAK1),which is an upstream signaling molecule required for IKKα/β,JNK and p38 activation.Conclusion: FLZ inhibited the LPS-induced production of inflammatory mediators at least partly through the downregula-tion of the TAK-IKK and TAK-JNK/p38MAPK pathways.
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