In Vitro and In Vivo Evidence for Anti-Inflammatory Properties of 2-Methoxyestradiol

Abstract

2-Methoxyestradiol (2MEO) is an endogenous metabolite of 17␤-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-␥ 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 LPSinduced acute lung inflammation in mice was also examined. 2MEO suppressed J774 macrophage interleukin-6 and prostaglandin E 2 production (by 30 and 47%, respectively, at 10 M) and human monocyte tumor necrosis factor-␣ production (by 60% at 3 M). Estradiol had no effect on J774 macrophage activation, nor did the estrogen receptor antagonist 7␣-[9- [(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17␤-diol (ICI 182,780) prevent the effects of 2MEO. The actions of 2MEO were not mimicked by the microtubuleinterfering 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 (ϳ54%) by treatment with 2MEO (150 mg ⅐ kg Ϫ1 ) or dexamethasone (1 mg ⅐ kg Ϫ1 ). 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.

Estrogen Metabolism by Cytochrome P450 1B1 Modulates the Hypertensive Effect of Angiotensin II in Female Mice

“…Further studies will determine the site of relationship between CYP1B1 and NADPH oxidase in the brain. Moreover, in view of the critical role of innate and adaptive immune cell systems and inflammation in Ang II-induced hypertension (54, 55) and the findings that estrogen and 2-MeE2 inhibit activation of immune cells and inflammation (56, 57) raise the possibility that these actions of estrogen and 2-MeE2 might contribute to the diminished effect of Ang II to increase BP and associated cardiovascular pathological changes in female mice.…”

Gonadal hormones and oxidative stress interaction differentially affects survival of male and female mice after lungKlebsiella Pneumoniaeinfection

“…In several animal models, male and female gonadal hormones have been previously implicated in sex differences in respiratory anatomy (31, 37), physiology (29, 38), in responses to diverse pathogens (29), and in lung inflammatory response (16, 39–41). In animal models, gonadal hormones exhibit the following effects: 1) alter markers of oxidative stress (42), 2) modulate oxidative stress response (43), 3) regulate synthesis of antioxidants (44), 4) modulate cytokine production, 5) regulate expression of macrophage surface receptors, such as CD14 and TLR4, and 6) contribute to sex differences in immune response under normal and pathologic conditions (45–47).…”

2-Methoxyestradiol inhibits experimental autoimmune encephalomyelitis through suppression of immune cell activation

“…In addition to its antiproliferative and antimitogenic effects, 2ME2 also appears to possess anti-inflammatory activity in mice (20,40), although the mechanism of action remains unclear.…”