Rosiglitazone Regulates TLR4 and Rescues HO-1 and NRF2 Expression in Myometrial and Decidual Macrophages in Inflammation-Induced Preterm Birth
Rosiglitazone Regulates TLR4 and Rescues HO-1 and NRF2 Expression in Myometrial and Decidual Macrophages in Inflammation-Induced Preterm Birth
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DOI：
10.1177/1933719117697128
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发表时间：
2017-12-01
影响因子：
2.9
通讯作者：
Drewlo, Sascha
中科院分区：
文献类型：
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作者：
Kadam, Leena;Gomez-Lopez, Nardhy;Drewlo, Sascha
前言：炎症升高约占早产（PTB）病例的30%。我们以前报道过，在内毒素诱导的PTB小鼠模型中，靶向过氧化物酶体增殖物激活受体γ（PPAR）通路可降低PTB的发生率。在我们的模型中，已证实PPAR具有抗炎功能，其通过罗格列酮的激活显著下调全身炎症反应，并分别将PTB和死胎率降低30%和41%。氧化应激与炎症密不可分，罗格列酮具有抗氧化活性。因此，在本研究中，我们的目的是评估罗格列酮治疗是否具有炎症途径以外的作用，特别是在我们的模型中的抗氧化途径。（E16.5）用磷酸盐缓冲盐水（PBS）、罗格列酮（Rosi）、脂多糖（LPS; 10 μ g在200 μ L 1XPBS中），或LPS + Rosi（LPS注射后6小时）。收集子宫肌层和蜕膜组织，并使用磁性细胞分选和F4/80+抗体处理巨噬细胞分离。通过定量聚合酶链反应定量测定抗氧化因子Nrf 2和Ho-1以及LPS受体Tlr 4的表达水平。结果：LPS处理组大鼠子宫蜕膜和子宫肌层巨噬细胞中Ho-1和Nrf 2的表达均显著低于PBS对照组，而Tlr 4的表达则显著高于PBS对照组。结论：罗格列酮通过下调炎症反应和上调抗氧化反应来预防PTB的发生。
Introduction: Elevated inflammation accounts for approximately 30% of preterm birth (PTB) cases. We previously reported that targeting the peroxisome proliferator-activated receptor gamma (PPAR) pathway reduced the incidence of PTB in the mouse model of endotoxin-induced PTB. The PPAR has proven anti-inflammatory functions and its activation via rosiglitazone significantly downregulated the systemic inflammatory response and reduced PTB and stillbirth rate by 30% and 41%, respectively, in our model. Oxidative stress is inseparable from inflammation, and rosiglitazone has a reported antioxidative activity. In the current study, we therefore aimed to evaluate whether rosiglitazone treatment had effects outside of inflammatory pathway, specifically on the antioxidation pathway in our model.Methods: Pregnant C57BL/6J mice (E16.5) were treated with phosphate-buffered saline (PBS), rosiglitazone (Rosi), lipopolysaccharide (LPS; 10 mu g in 200 mu L 1XPBS), or LPS + Rosi (6 hours after the LPS injection). The myometrial and decidual tissues were collected and processed for macrophage isolation using magnetic cell sorting and F4/80+ antibody. Expression levels of antioxidative factorsNrf2 and Ho-1along with the LPS receptor Tlr4 were quantified by quantitative polymerase chain reaction. The protein levels were assessed by immunofluorescence staining.Results: Both the decidual and myometrial macrophages from the LPS-treated animals showed significantly lowered expression of Ho-1 and Nrf2 and higher expression of Tlr4 when compared to the PBS control group. The macrophages from the animals in the LPS + Rosi group had significantly elevated expression of Ho-1 and Nrf2 and downregulated expression of Tlr4 when compared to the LPS group.Conclusion: Rosiglitazone administration prevents PTB by downregulating inflammation and upregulating antioxidative response.