Lipopolysaccharide Downregulates 11β-Hydroxysteroid Dehydrogenase 2 Expression through Inhibiting Peroxisome Proliferator-Activated Receptor-γ in Placental Trophoblasts
Lipopolysaccharide Downregulates 11β-Hydroxysteroid Dehydrogenase 2 Expression through Inhibiting Peroxisome Proliferator-Activated Receptor-γ in Placental Trophoblasts
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脂多糖通过抑制胎盘滋养细胞中过氧化物酶体增殖物激活受体-γ 下调 11β-羟基类固醇脱氢酶 2 表达
DOI：
10.4049/jimmunol.1900132
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发表时间：
2019-09-01
影响因子：
4.4
通讯作者：
Xu, De-Xiang
中科院分区：
文献类型：
--
作者：
Fu, Lin;Chen, Yuan-Hua;Xu, De-Xiang
越来越多的人认识到过量糖皮质激素会导致胎儿宫内生长受限（IUGR）。胎盘11 β-羟基类固醇脱氢酶2（11 β-HSD 2）是一种糖皮质激素催化酶，可阻止活性糖皮质激素从母体循环进入胎儿，从而防止IUGR。以往的研究表明，妊娠期LPS暴露可导致胎儿IUGR。本研究的目的是研究LPS对小鼠胎盘和人胎盘滋养层细胞中11 β-HSD 2的影响。妊娠ICR（CD-1）小鼠在妊娠第16天腹膜内注射LPS（200 μ g/kg）。正如预期的那样，妊娠期LPS暴露下调了小鼠胎盘中的11 β-HSD 2。在体外，LPS下调人胎盘滋养层细胞中的11 β-HSD 2。另外的实验表明，激活NF-κ B的LPS抑制罗格列酮诱导的小鼠胎盘和人胎盘滋养层中过氧化物酶体增殖物激活受体γ（PPAR γ）的激活。此外，NF-κ B p65敲低和特异性NF-κ B抑制剂减弱LPS诱导的人胎盘滋养层细胞中PPAR γ核转位的抑制。此外，NF-κ B p65敲低减弱了LPS诱导的人胎盘滋养层细胞中11 β-HSD 2的下调。在机械上，LPS促进胎盘滋养层细胞的细胞质和细胞核中NF-κ B p65和PPAR γ之间的物理相互作用。最后，罗格列酮，一种过氧化物酶体增殖物激活受体γ激动剂，预处理，部分减轻LPS诱导的胎儿体重和顶臀长度的减少。综上所述，这些结果表明LPS通过抑制胎盘滋养层中的PPAR γ下调11 β-HSD 2。胎盘11 β-HSD 2下调可能部分导致LPS诱导的胎儿IUGR。
It is increasingly recognized that excessive glucocorticoids induce fetal intrauterine growth restriction (IUGR). Placental 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD2), a glucocorticoid-catalyzing enzyme, prevents active glucocorticoids from maternal circulation into the fetus, thus protecting against IUGR. Previous studies demonstrated gestational LPS exposure caused fetal IUGR. The aim of the current study was to investigate the effects of LPS on 11 beta-HSD2 in mice placentas and human placental trophoblasts. Pregnant ICR(CD-1) mice were i.p. injected with LPS (200 mu g/kg) on gestational day 16. As expected, gestational LPS exposure downregulated 11 beta-HSD2 in mice placentas. In vitro, LPS downregulated 11 beta-HSD2 in human placental trophoblasts. Additional experiment showed that LPS, which activated NF-kappa B, suppressed rosiglitazone-induced activation of peroxisome proliferator-activated receptor-y (PPAR gamma) in mice placentas and human placental trophoblasts. Moreover, NF-kappa B p65 knockdown and specific NF-kappa B inhibitor attenuated LPS-induced suppression of PPAR gamma nuclear translocation in human placental trophoblasts. In addition, NF-kappa B p65 knockdown attenuated LPS-induced downregulation of 11 beta-HSD2 in human placental trophoblasts. Mechanically, LPS promoted physical interaction between NF-kappa B p65 and PPAR gamma in the cytoplasm and nucleus of placental trophoblasts. Finally, pretreatment with rosiglitazone, a PPAR gamma agonist, partially alleviated LPS-induced reduction of fetal weight and crown-rump length. Taken together, these results suggest that LPS downregulates 11 beta-HSD2 through suppressing PPAR gamma in placental trophoblasts. Placental 11 beta-HSD2 downregulation may contribute partially to LPS-induced fetal IUGR.