4-Hydroxykobusin Inhibits the Induction of Nitric Oxide Synthase by Inhibiting NF-.KAPPA.B and AP-1 Activation

Abstract

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-κB (NF-κB) 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-κB and AP-1 activation.