17α-雌二醇体外抑制炎症的作用。
The effects of 17 alpha-estradiol to inhibit inflammation in vitro.
机构信息
Biomedical Sciences Dept, Diabetes and Obesity Research Division, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
Obesity and Comorbidities Research Center (OCRC), Institute of Biology, State University of Campinas-UNICAMP, Campinas, SP, Brazil.
出版信息
Biol Sex Differ. 2017 Sep 6;8(1):30. doi: 10.1186/s13293-017-0151-9.
BACKGROUND
17 Alpha-estradiol (17 α-E2) is a natural, non-feminizing stereoisomer of 17 beta-estradiol (17 β-E2). Whereas much is known about the physiological effects of 17 β-E2, much less is known about 17 α-E2. For example, 17 β-E2 exerts anti-inflammatory effects in neurons and adipocytes through binding and activation of estrogen receptor alpha (ERα); however, if 17 α-E2 has similar effects on inflammation is currently unknown.
METHODS
To begin to address this, we analyzed the ability of 17 α-E2 and 17 β-E2 to suppress lipopolysaccharide (LPS)-induced inflammation in vitro using embryonic fibroblast cells (MEF) from wild type and total body ERα (ERKO) male and female mice. Additionally, we further probed if there were sex differences with respect to the effects of E2s using primary pre-adipocyte cells from C57BL/6J male and female mice. Also, we probed mechanistically the effects of E2s in fully differentiated 3T3-L1 cells.
RESULTS
Both E2s decreased LPS-induced markers of inflammation Tnf-α and Il-6, and increased the anti-inflammatory markers Il-4 and IL-6 receptor (Il-6ra) in MEF cells. To begin to understand the mechanisms by which both E2's mediate their anti-inflammatory effects, we probed the role of ERα using two methods. First, we used MEF cells from ERKO mice and found reductions in ERα diminished the ability of 17 α-E2 to suppress Tnf-α in female but not in male cells, demonstrating a sexual dimorphism in regard to the role of ERα to mediate 17 α-E2's effects. Second, we selectively reduced the expression of ERα in 3T3-L1 cells using siRNA and found reductions in ERα diminished the ability of both E2s to suppress Tnf-α and Il-6 expression. Lastly, to determine the mechanisms by which E2s reduce inflammation, we explored the role of NFκB-p65 and found both E2s decreased NFκB-p65 expression.
CONCLUSIONS
In conclusion, we demonstrate for the first time that 17 α-E2, as well as 17 β-E2, suppresses inflammation through their effects on ERα and NFκB-p65.
背景
17α-雌二醇（17α-E2）是 17β-雌二醇（17β-E2）的一种天然、非女性化的立体异构体。虽然人们对 17β-E2 的生理作用了解很多，但对 17α-E2 的了解却很少。例如，17β-E2 通过与雌激素受体α（ERα）结合和激活，在神经元和脂肪细胞中发挥抗炎作用；然而，目前尚不清楚 17α-E2 是否对炎症有类似的作用。
方法
为了开始解决这个问题，我们使用来自野生型和全身 ERα（ERKO）雄性和雌性小鼠的胚胎成纤维细胞（MEF），分析了 17α-E2 和 17β-E2 抑制脂多糖（LPS）诱导的体外炎症的能力。此外，我们还进一步研究了 E2 对 C57BL/6J 雄性和雌性小鼠原代前脂肪细胞炎症作用的性别差异。此外，我们还研究了 E2 在完全分化的 3T3-L1 细胞中的作用机制。
结果
两种 E2 均降低 LPS 诱导的炎症标志物 TNF-α 和 IL-6，增加抗炎标志物 IL-4 和 IL-6 受体（IL-6ra）在 MEF 细胞中的表达。为了开始了解两种 E2 介导其抗炎作用的机制，我们使用两种方法研究了 ERα 的作用。首先，我们使用 ERKO 小鼠的 MEF 细胞，发现 ERα 的缺失减少了 17α-E2 抑制 TNF-α 的能力，但在雄性细胞中却没有，这表明 ERα 在介导 17α-E2 作用方面存在性别二态性。其次，我们使用 siRNA 选择性降低 3T3-L1 细胞中 ERα 的表达，发现 ERα 的减少降低了两种 E2 抑制 TNF-α 和 IL-6 表达的能力。最后，为了确定 E2 降低炎症的机制，我们研究了 NFκB-p65 的作用，发现两种 E2 均降低 NFκB-p65 的表达。
结论
综上所述，我们首次证明 17α-E2 和 17β-E2 均通过 ERα 和 NFκB-p65 抑制炎症。
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