Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: Potential role of reactive oxygen intermediates and lipid peroxidation

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin f ound in grapes, fruits, and root extracts of the weed Polygonum cuspidatum, exhibits anti-inflammatory, cell growth-modulatory, and anticarcinogenic e ffects. How this chemical produces these effects is not known, but it may w ork by suppressing NP-kappa B, a nuclear transcription factor that regulate s the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this study, we investigated the effect of resveratr ol on NF-kappa B activation induced by various inflammatory agents, Resvera trol blocked TNF-induced activation of NF-kappa B in a dose- and time-depen dent manner. Resveratrol also suppressed TNF-induced phosphorylation and nu clear translocation of the p65 subunit of NF-kappa B, and NF-kappa B-depend ent reporter gene transcription, Suppression of TNF-induced NF-kappa B acti vation by resveratrol was not restricted to myeloid cells (U-937); it was a lso observed in lymphoid (Jurkat) and epithelial (HeLa and H4) cells. Resve ratrol also blocked NF-kappa B activation induced by PMA, LPS, H2O2, okadai c acid, and ceramide, The suppression of NF-kappa B coincided with suppress ion of AP-1, Resveratrol also inhibited the TNF-induced activation of mitog en-activated protein kinase kinase and c-Jun N-terminal kinase and abrogate d TNF-induced cytotoxicity and caspase activation. Both reactive oxygen int ermediate generation and lipid peroxidation induced by TNF were suppressed by resveratrol. Resveratrol's anticarcinogenic, anti-inflammatory, and grow th-modulatory effects may thus be partially ascribed to the inhibition of a ctivation of NF-kappa B and AP-1 and the associated kinases.