Ashikawa Kazuhiro, Majumdar Sekhar, Banerjee Sanjeev, Bharti Alok C, Shishodia Shishir, Aggarwal Bharat B
Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
J Immunol. 2002 Dec 1;169(11):6490-7. doi: 10.4049/jimmunol.169.11.6490.
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.
白皮杉醇是一种具有抗炎、免疫调节和抗增殖作用的芪类化合物，已被证明可干扰细胞因子信号通路。此前，我们已经表明白藜芦醇可抑制核转录因子NF-κB的激活。白皮杉醇先前被报道为蛋白酪氨酸激酶Syk的选择性抑制剂，其结构与白藜芦醇同源。我们研究了白皮杉醇是否也能抑制NF-κB的激活。用白皮杉醇处理人髓细胞可抑制TNF诱导的NF-κB的DNA结合活性。相比之下，芪类化合物或rhaponticin（白皮杉醇的另一种类似物）则没有作用，这表明羟基起关键作用。白皮杉醇的作用并不局限于髓细胞，因为TNF诱导的NF-κB激活在淋巴细胞和上皮细胞中也受到抑制。白皮杉醇还可抑制由H₂O₂、PMA、LPS、冈田酸和神经酰胺激活的NF-κB。白皮杉醇可消除TNF诱导的NF-κB依赖性报告基因以及基质金属蛋白酶-9、环氧化酶-2和细胞周期蛋白D1的表达。在研究其作用机制时，我们发现白皮杉醇可抑制TNF诱导的IκBα磷酸化、p65磷酸化、p65核转位和IκBα激酶激活，但对IκBα降解没有显著影响。白皮杉醇在缺失Syk的细胞中也能抑制NF-κB，这表明该激酶未参与其中。总体而言，我们的结果清楚地表明芪类化合物的羟基至关重要，并且四羟基芪类化合物白皮杉醇可通过抑制IκBα激酶和p65磷酸化来抑制多种炎症因子诱导的NF-κB激活。
