Cudratricusxanthone A from Cudrania tricuspidata suppresses pro-inflammatory mediators through expression of anti-inflammatory heme oxygenase-1 in RAW264.7 macrophages

Cudratricusxanthone A (CTXA), isolated from the roots of Cudrania tricuspidata Bureau (Moraceae) has an isoprenylated xanthone skeleton that is known to exert a variety of biological activities. In the present study, we demonstrated that CTXA inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide (NO) synthase (iNOS) expression, and thereby reduced COX-2-derived prostaglandin E2 (PGE2) and iNOS-derived NO production in lipopolysaccharide (LPS)-stimulated macrophages. Similarly, CTXA suppressed tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) production. Moreover, CTXA inhibited the induced phosphorylation and degradation of IκB-α as well as the LPS-induced increase in p65 in the nuclear fraction of macrophages. CTXA also induced heme oxygenase-1 (HO-1) expression and increased heme oxygenase (HO) activity in RAW264.7 macrophages. We also demonstrated that the effects of CTXA on LPS-induced PGE2, NO, TNF-α, and IL-1β production were partially reversed by the HO-1 inhibitor tin protoporphyrin, suggesting that CTXA-induced HO-1 expression was partly responsible for the resulting anti-inflammatory effects of the drug. Thus CTXA was shown to be an effective HO-1 inducer, capable of inhibiting macrophage-derived pro-inflammatory mediators.