cyclin-d1 and 3-3--4-5--tetrahydroxystilbene

Macrophage proliferation can be stimulated by phagocytosis and by cross-linking of Fcgamma receptors (FcgammaR). In this study, we investigated the role of FcgammaR and the signaling cascades that link FcgammaR activation to cell cycle progression. This effect was mediated by the activating FcgammaR, including FcgammaRI and III, via their Fcgamma subunit. Further investigation revealed that the cell cycle machinery was activated by FcgammaR cross-linking through downstream signaling events. Specifically, we identified the extracellular signal-regulated kinase (ERK) signaling pathway as a mediator of signals from FcgammaR activation to cyclin D1 expression, because cyclin D1 expression associated with FcgammaR cross-linking was attenuated by specific inhibitors of the ERK1/2 signaling pathway, PD98059 and U0126 and the spleen tyrosine kinase (Syk) inhibitor, Piceatannol. Our findings establish a link between the ERK activation and cell cycle signaling pathways, thus providing a causal mechanism by which FcgammaR activation produces a mitogenic effect that stimulates macrophage proliferation. Macrophage mitosis following FcgammaR activation could potentially affect the outcome of macrophage interactions with intracellular pathogens. In addition, our results suggest the possibility of new treatment options for certain infectious diseases, chronic inflammatory diseases, and leukemias based on interference with FcgammaR-stimulated macrophage cell proliferation.

Topics: Animals; Blotting, Western; Bone Marrow Cells; Butadienes; Cell Cycle; Cell Line; Cell Proliferation; Cyclin D1; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Flow Cytometry; Intracellular Signaling Peptides and Proteins; Macrophages; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitriles; Protein-Tyrosine Kinases; Receptors, IgG; Stilbenes; Syk Kinase

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