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The Journal of Immunology, 2002, 169: 6490-6497.
Copyright © 2002 by The American Association of Immunologists

Piceatannol Inhibits TNF-Induced NF-{kappa}B Activation and NF-{kappa}B-Mediated Gene Expression Through Suppression of I{kappa}B{alpha} Kinase and p65 Phosphorylation1

Kazuhiro Ashikawa, Sekhar Majumdar, Sanjeev Banerjee, Alok C. Bharti, Shishir Shishodia and Bharat B. Aggarwal2

Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030

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-{kappa}B. Piceatannol, previously reported as a selective inhibitor of protein tyrosine kinase Syk, is structurally homologous to resveratrol. Whether piceatannol can also suppress NF-{kappa}B activation was investigated. The treatment of human myeloid cells with piceatannol suppressed TNF-induced DNA binding activity of NF-{kappa}B. 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-{kappa}B activation was also suppressed in lymphocyte and epithelial cells. Piceatannol also inhibited NF-{kappa}B activated by H2O2, PMA, LPS, okadaic acid, and ceramide. Piceatannol abrogated the expression of TNF-induced NF-{kappa}B-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 I{kappa}B{alpha} phosphorylation, p65 phosphorylation, p65 nuclear translocation, and I{kappa}B{alpha} kinase activation, but had no significant effect on I{kappa}B{alpha} degradation. Piceatannol inhibited NF-{kappa}B 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-{kappa}B activation induced by various inflammatory agents through inhibition of I{kappa}B{alpha} kinase and p65 phosphorylation.




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