Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
J Pharmacol Exp Ther. 2011 Mar;336(3):962-72. doi: 10.1124/jpet.110.174854. Epub 2010 Dec 21.
2-Methoxyestradiol (2MEO) is an endogenous metabolite of 17β-estradiol that interacts with estrogen receptors and microtubules. It has acute anti-inflammatory activity in animal models that is not attributable to known antiproliferative or antiangiogenic actions. Because macrophages are central to the innate inflammatory response, we examined whether suppression of macrophage activation by 2MEO could account for some of its anti-inflammatory effects. Inflammatory mediator production stimulated by lipopolysaccharide (LPS) and interferon-γ in the J774 murine macrophage cell line or human monocytes was measured after treatment with 2MEO or the anti-inflammatory agent dexamethasone. The effect of these agents on LPS-induced acute lung inflammation in mice was also examined. 2MEO suppressed J774 macrophage interleukin-6 and prostaglandin E₂ production (by 30 and 47%, respectively, at 10 μM) and human monocyte tumor necrosis factor-α production (by 60% at 3 μM). Estradiol had no effect on J774 macrophage activation, nor did the estrogen receptor antagonist 7α-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17β-diol (ICI 182,780) prevent the effects of 2MEO. The actions of 2MEO were not mimicked by the microtubule-interfering agents colchicine or paclitaxel. In mice exposed to LPS, bronchoalveolar lavage protein content, a measure of vascular leak and epithelial injury, was reduced to a comparable extent (~54%) by treatment with 2MEO (150 mg · kg⁻¹) or dexamethasone (1 mg · kg⁻¹). In addition, 2MEO reduced LPS-induced interleukin-6 gene expression. Thus, 2MEO modulates macrophage activation in vitro and has high-dose acute anti-inflammatory activity in vivo. These findings are consistent with the acute anti-inflammatory actions of 2MEO being mediated in part by the suppression of macrophage activation.
2-甲氧基雌二醇（2MEO）是 17β-雌二醇的内源性代谢物，可与雌激素受体和微管相互作用。它在动物模型中具有急性抗炎活性，而这种活性与已知的抗增殖或抗血管生成作用无关。由于巨噬细胞是先天炎症反应的核心，因此我们研究了 2MEO 对巨噬细胞激活的抑制作用是否可以解释其部分抗炎作用。在 J774 鼠巨噬细胞系或人单核细胞中，用脂多糖（LPS）和干扰素-γ刺激后，测量 2MEO 或抗炎剂地塞米松处理后炎症介质的产生。还检查了这些药物对 LPS 诱导的小鼠急性肺炎症的影响。2MEO 抑制 J774 巨噬细胞白细胞介素-6 和前列腺素 E₂的产生（在 10 μM 时分别为 30%和 47%），并抑制人单核细胞肿瘤坏死因子-α的产生（在 3 μM 时为 60%）。雌二醇对 J774 巨噬细胞的激活没有影响，雌激素受体拮抗剂 7α-[9-[(4,4,5,5,5-五氟戊基)亚磺酰基]壬基]雌-1,3,5(10)-三烯-3,17β-二醇（ICI 182,780）也不能阻止 2MEO 的作用。微管干扰剂秋水仙碱或紫杉醇不能模拟 2MEO 的作用。在 LPS 暴露的小鼠中，支气管肺泡灌洗液蛋白含量（一种血管渗漏和上皮损伤的测量指标）通过用 2MEO（150 mg·kg⁻¹）或地塞米松（1 mg·kg⁻¹）治疗，降低至相当程度（~54%）。此外，2MEO 降低了 LPS 诱导的白细胞介素-6 基因表达。因此，2MEO 在体外调节巨噬细胞激活，并且在体内具有高剂量的急性抗炎活性。这些发现与 2MEO 的急性抗炎作用部分通过抑制巨噬细胞激活介导的观点一致。
