Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression.
Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression.
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发表时间：
1995-08
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通讯作者：
M. Gerritsen;W. Carley;G. Ranges;C. Shen;Stacie A. Phan;G. Ligon;C. Perry
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作者：
M. Gerritsen;W. Carley;G. Ranges;C. Shen;Stacie A. Phan;G. Ligon;C. Perry
用细胞因子如白细胞介素-1、肿瘤坏死因子-α（TNF-α）或干扰素-γ处理人内皮细胞诱导内皮细胞表面上特异性白细胞粘附分子的表达。干扰白细胞粘附或粘附蛋白上调是重要的治疗靶点，如在各种动物模型和患者中针对这些配体的中和抗体的有效抗炎作用所证明的。在本研究中，我们报告，共治疗的人内皮细胞与某些羟基黄酮和黄烷醇块姜黄素诱导的ICAM-1，VCAM-1，和E-选择素表达的人内皮细胞。芹菜素是最有效的黄酮类化合物之一，对粘附蛋白表达具有剂量和时间依赖性的可逆作用，并在转录水平上抑制粘附蛋白的上调。芹菜素还抑制IL-1 α诱导的前列腺素合成和TNF-α诱导的IL-6和IL-8的产生，这表明羟基黄酮类化合物可能作为芹菜素诱导的基因表达的一般抑制剂。尽管芹菜素不能抑制TNF-α诱导的NF-κ B核转位（p50（NF-κ B1）/p65（RelA）），但我们发现这种类黄酮确实能抑制TNF-α诱导的SW 480细胞中的β-半乳糖苷酶活性，该细胞稳定转染了由四个NF-κ B元件驱动的β-半乳糖苷酶报告基因构建体，这表明其对NF-κ B转录激活有作用。芹菜素处理的内皮细胞中，白细胞粘附到姜黄素处理的内皮细胞被阻断。最后，芹菜素对角叉菜胶诱导的大鼠足肿胀和小鼠迟发型超敏反应表现出有效的抗炎活性。我们的结论是，黄酮类化合物提供了重要的治疗潜力，用于治疗各种炎症性疾病，涉及白细胞粘附和贩运的增加。
Treatment of human endothelial cells with cytokines such as interleukin-1, tumor necrosis factor-alpha (TNF-alpha) or interferon-gamma induces the expression of specific leukocyte adhesion molecules on the endothelial cell surface. Interfering with either leukocyte adhesion or adhesion protein upregulation is an important therapeutic target as evidenced by the potent anti-inflammatory actions of neutralizing antibodies to these ligands in various animal models and in patients. In the present study we report that cotreatment of human endothelial cells with certain hydroxyflavones and flavanols blocks cytokine-induced ICAM-1, VCAM-1, and E-selectin expression on human endothelial cells. One of the most potent flavones, apigenin, exhibited a dose- and time-dependent, reversible effect on adhesion protein expression as well as inhibiting adhesion protein upregulation at the transcriptional level. Apigenin also inhibited IL-1 alpha-induced prostaglandin synthesis and TNF-alpha-induced IL-6 and IL-8 production, suggesting that the hydroxyflavones may act as general inhibitors of cytokine-induced gene expression. Although apigenin did not inhibit TNF-alpha-induced nuclear translocation of NF-kappa B(p50(NFKB1)/p65(RelA)) we found this flavonoid did inhibit TNF-alpha induced beta-galactosidase activity in SW480 cells stably transfected with a beta-galactosidase reporter construct driven by four NF-kappa B elements, suggesting an action on NF-kappa B transcriptional activation. Adhesion of leukocytes to cytokine-treated endothelial cells was blocked in endothelial cells cotreated with apigenin. Finally, apigenin demonstrated potent anti-inflammatory activity in carrageenan induced rat paw edema and delayed type hypersensitivity in the mouse. We conclude that flavonoids offer important therapeutic potential for the treatment of a variety of inflammatory diseases involving an increase in leukocyte adhesion and trafficking.