Mukherjee Tapan K, Nathan Lauren, Dinh Hillary, Reddy Srinivasa T, Chaudhuri Gautam
Department of Obstetrics and Gynecology, University of California, Los Angeles, California 90095-1740, USA.
J Biol Chem. 2003 Apr 4;278(14):11746-52. doi: 10.1074/jbc.M207800200. Epub 2003 Jan 23.
17-beta estradiol (17-beta E(2)) attenuates the expression of vascular cell adhesion molecule 1 (VCAM-1) in vivo at physiological levels (pg/ml), whereas supraphysiological concentrations of 17-beta E(2) (ng/ml) are required in vitro. We assessed whether a metabolite of estrogen, which could only be generated in vivo, might be a more potent inhibitor of VCAM-1 expression and thereby explain this discrepancy. We report here that 17-epiestriol, an estrogen metabolite and a selective estrogen receptor (ER) beta agonist, is approximately 400x more potent than 17-beta E(2) in suppressing tumor necrosis factor (TNF) alpha-induced VCAM-1 mRNA as well as protein expression in human umbilical vein endothelial cells. Genistein, an ERbeta agonist, at low concentrations (1 and 10 nm) also suppressed TNFalpha-induced VCAM-1 mRNA expression. These actions of 17-epiestriol and genistein were significantly attenuated in the presence of the estrogen receptor antagonist ICI-182780. Other estrogenic compounds such as ethinyl estradiol and estrone did not have any effect on TNFalpha-induced VCAM-1 expression at the concentrations tested. We further show that, 1) 17-epiestriol induces the expression of endothelial nitric-oxide synthase mRNA and protein, 2) 17-epiestriol prevents TNFalpha-induced migration of NFkappaB into the nucleus, 3) N(G)-nitro-l-arginine methyl ester, an inhibitor of NO synthesis, abolishes 17-epiestriol-mediated inhibition of TNFalpha-induced VCAM-1 expression and migration of NFkappaB from the cytoplasm to the nucleus. Our results indicate that 17-epiestriol is more potent than 17-beta E(2) in suppressing TNFalpha-induced VCAM-1 expression and that this action is modulated at least in part through NO.
17-β雌二醇（17-β E₂）在生理水平（皮克/毫升）下可在体内减弱血管细胞黏附分子1（VCAM-1）的表达，而在体外则需要超生理浓度的17-β E₂（纳克/毫升）。我们评估了一种仅能在体内生成的雌激素代谢产物是否可能是VCAM-1表达的更有效抑制剂，从而解释这种差异。我们在此报告，17-表雌三醇，一种雌激素代谢产物和选择性雌激素受体（ER）β激动剂，在抑制人脐静脉内皮细胞中肿瘤坏死因子（TNF）α诱导的VCAM-1 mRNA以及蛋白表达方面比17-β E₂强约400倍。染料木黄酮，一种ERβ激动剂，在低浓度（1和10纳米）时也抑制TNFα诱导的VCAM-1 mRNA表达。在雌激素受体拮抗剂ICI-182780存在的情况下，17-表雌三醇和染料木黄酮的这些作用显著减弱。其他雌激素化合物如乙炔雌二醇和雌酮在测试浓度下对TNFα诱导的VCAM-1表达没有任何影响。我们进一步表明，1）17-表雌三醇诱导内皮型一氧化氮合酶mRNA和蛋白的表达，2）17-表雌三醇阻止TNFα诱导的NFκB向细胞核迁移，3）NO合成抑制剂N(G)-硝基-L-精氨酸甲酯消除了17-表雌三醇介导的对TNFα诱导的VCAM-1表达以及NFκB从细胞质向细胞核迁移的抑制作用。我们的结果表明，17-表雌三醇在抑制TNFα诱导的VCAM-1表达方面比17-β E₂更有效，并且这种作用至少部分是通过NO调节的。
