科研之友
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摘要
Context and Objective: During their reproductive years, women are generally protected from cardiovascular disease events by their estrogen-replete status. Our starting hypothesis was that lower estrogen levels after menopause are associated with macrophage activation profiles skewed toward proinflammatory phenotypes. Research Design and Setting: This was an in vitro and ex vivo study in human blood-derived macrophages. Subjects: We obtained blood from 12 healthy male donors for the in vitro study and from 5 premenopausal and 8 postmenopausal women for the ex vivo study. Outcome: We measured macrophage immunophenotypes in the resting state and after activation with M1-associated (lipopolysaccharide [LPS]/interferon-gamma[IFN-gamma]) or M2-associated (IL-4/IL-13) stimuli and expression of estrogen receptors (ERs) and other transcription factors. Results: Unpolarized macrophages expressed both ER alpha and ER beta, and ER alpha but not ER beta levels were decreased by M1 stimuli. LPS/IFN-gamma also induced down-regulation of CD163 and CD206, markers of alternative activation, and increased cell-bound TNF-alpha and IL-10. These effects were prevented by 17 beta-estradiol treatment through impaired nuclear factor-kappa B liberation. In agreement with a role for 17 beta-estradiol in attenuating the inflammatory response, M1/M2 subpopulations in monocytes and unstimulated macrophages from premenopausal and postmenopausal donors were similar. In contrast, M2 activation appeared to be blunted in macrophages from postmenopausal women, leading to an increased M1/M2 response ratio. Conclusions: Estrogen treatment prevented LPS/IFN-gamma action on human M2 macrophage markers and cytokine production, whereas menopausal estrogen loss was associated with an impaired response to alternative activation, suggesting that these mechanisms affect the cardiovascular risk profile in relation to menopausal status.
- 出版日期2015-1
