Hypoestoxide, a novel anti-inflammatory natural diterpene, inhibits the activity of I kappa B kinase

Most inflammatory agents activate nuclear factor-kappaB (NF-kappaB), result ing in induction of genes coding for cytokines, chemokines, and enzymes inv olved in amplification and perpetuation of inflammation. Hypoestoxide (a bi cycle [9,3,1] pentadecane) is a diterpene from Hypoestes rosea, a tropical shrub in the family Acanthacea, several members of which are used in folk m edicine in Nigeria. Here, we demonstrate that hypoestoxide (HE) abrogates t he production of proinflammatory cytokines (IL-1 beta, IL-6, and TNF-alpha) in lipopolysaccharide (LPS)-activated normal human peripheral blood mononu clear cells, Moreover, HE inhibits the production of nitric oxide (NO) by I L-1 beta- or IL-17-stimulated normal human chondrocytes. In vivo, oral admi nistration of HE to mice significantly ameliorated hind paw edema induced b y antibodies to type II collagen plus LPS. Furthermore, topical administrat ion of HE to mice also significantly inhibited phorbol ester-induced ear in flammation. The anti-inflammatory activity of HE may be due in part to its ability to inhibit NF-kappaB activation through direct inhibition of I kapp aB kinase (IKK) activity, Thus, HE could be useful in treating various infl ammatory diseases and may represent a prototype of a novel class of IKK inh ibitors. (C) 2001 Academic Press.