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Compound FLZ inhibits lipopolysaccharide-induced inflammatory effects via down-regulation of the TAK-IKK and TAK-JNK/p38MAPK pathways in RAW264.7 macrophages.


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.

SUBMITTER: Pang HY 

PROVIDER: S-EPMC4002472 | BioStudies | 2009-01-01

SECONDARY ACCESSION(S): 10.1038/aps.2008.29

REPOSITORIES: biostudies

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