okadaic-acid and 3-3--4-5--tetrahydroxystilbene

Piceatannol is an anti-inflammatory, immunomodulatory, and anti-proliferative stilbene that has been shown to interfere with the cytokine signaling pathway. Previously, we have shown that resveratrol suppresses the activation of the nuclear transcription factor NF-kappaB. Piceatannol, previously reported as a selective inhibitor of protein tyrosine kinase Syk, is structurally homologous to resveratrol. Whether piceatannol can also suppress NF-kappaB activation was investigated. The treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-kappaB. In contrast, stilbene or rhaponticin (another analog of piceatannol) had no effect, suggesting the critical role of hydroxyl groups. The effect of piceatannol was not restricted to myeloid cells, as TNF-induced NF-kappaB activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-kappaB activated by H(2)O(2), PMA, LPS, okadaic acid, and ceramide. Piceatannol abrogated the expression of TNF-induced NF-kappaB-dependent reporter gene and of matrix metalloprotease-9, cyclooxygenase-2, and cyclin D1. When examined for the mechanism, we found that piceatannol inhibited TNF-induced IkappaBalpha phosphorylation, p65 phosphorylation, p65 nuclear translocation, and IkappaBalpha kinase activation, but had no significant effect on IkappaBalpha degradation. Piceatannol inhibited NF-kappaB in cells with deleted Syk, indicating the lack of involvement of this kinase. Overall, our results clearly demonstrate that hydroxyl groups of stilbenes are critical and that piceatannol, a tetrahydroxystilbene, suppresses NF-kappaB activation induced by various inflammatory agents through inhibition of IkappaBalpha kinase and p65 phosphorylation.

Topics: Active Transport, Cell Nucleus; Anti-Inflammatory Agents, Non-Steroidal; Base Sequence; Cell Line; Ceramides; Cyclin D1; Cyclooxygenase 2; DNA; Enzyme Inhibitors; Enzyme Precursors; Gene Expression; HeLa Cells; Humans; Hydrogen Peroxide; I-kappa B Kinase; Intracellular Signaling Peptides and Proteins; Isoenzymes; Jurkat Cells; Lipopolysaccharides; Matrix Metalloproteinase 9; Membrane Proteins; NF-kappa B; Okadaic Acid; Phosphorylation; Prostaglandin-Endoperoxide Synthases; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Stilbenes; Syk Kinase; Tetradecanoylphorbol Acetate; Transcription Factor RelA; Tumor Necrosis Factor-alpha