Inhibition of NF-kappaB Activation and INOS Induction by Ent-kaurane Diterpenoids in LPS-stimulated RAW264.7 Murine Macrophages

Xerophilusin A (1), xerophilusin B (2), longikaurin B (3), and xerophilusin F (4) from Isodon xerophylus inhibit LPS-induced NO production in RAW 264.7 macrophages, with IC(50) values of 0.60, 0.23, 0.44, and 0.67 muM, respectively, and they all inhibited mRNA production in these same cells. They decreased the luciferase activity in RAW 264.7 cells transiently transfected with the NF-kappaB-dependent luciferase reporter, with IC(50) values of 1.8, 0.7, 1.2, and 1.6 muM, respectively. Compounds 1-3 reduced NF-kappaB activation, with compound 4 showing no effect, but p65 translocation from the cytoplasm to the nucleus and the LPS-induced degradation of IkappaB were inhibited by all four test compounds. These findings indicate that ent-kauranes are potential anti-inflammatory agents, with a specific mechanism in which both the inhibition of NF-kappaB translocation and the consequent decrease of pro-inflammatory mediators are implicated.