4-Hydroxykobusin inhibits the induction of nitric oxide synthase by inhibiting NF-kappaB and AP-1 activation.
We recently isolated a novel lignan, 4-hydroxykobusin from Geranium thunbergii (Liu et al., Arch. Pharm. Res., 29, 1109-1113, 2006). Here, we studied its effect on the expression of inducible nitric oxide synthase (iNOS) gene in RAW264.7 cells. 4-Hydroxykobusin inhibited nitric oxide (NO) production in a concentration-dependent manner and blocked the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS). To identify the mechanistic basis for its inhibition of iNOS induction, we examined the effect of 4-hydroxykobusin on the transactivation of iNOS gene by luciferase reporter activity using -1.59 kb flanking region. The lignan suppressed the reporter gene activity and the LPS-induced reporter activations of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) were also significantly blocked by 4-hydroxykobusin. These findings suggest that the inhibition of LPS-induced NO formation by 4-hydroxykobusin is due to its inhibition of NF-kappaB and AP-1 activation.
Pokharel
Yuba Raj
YR
BK21 Project Team, Chosun University, Gwangju, South Korea.
Liu
Qing-He
QH
Oh
Jae Wook
JW
Woo
Eun-Rhan
ER
Kang
Keon Wook
KW
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005562:Formazans / Q000378:metabolism; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter; D031315:Geranium / Q000737:chemistry; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008156:Luciferases / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation
C517925:4-hydroxykobusin; D005562:Formazans; D005663:Furans; D017705:Lignans; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010936:Plant Extracts; D013778:Tetrazolium Salts; D018808:Transcription Factor AP-1; C079782:MTT formazan; D008156:Luciferases; D052247:Nitric Oxide Synthase Type II