Glucocorticoids Sensitize Rat Placental Inflammatory Responses via Inhibiting Lipoxin A4 Biosynthesis1
Glucocorticoids Sensitize Rat Placental Inflammatory Responses via Inhibiting Lipoxin A4 Biosynthesis1
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DOI：
10.1095/biolreprod.113.116384
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发表时间：
2014-04
期刊：
影响因子：
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通讯作者：
Dongxin Zhang;Yong-sheng Li;Hui Peng;Haojing Liu;Qiong Cheng;Xue Cheng;P. Zeng;Ping Wu;Hongxiang Chen;Yinping Huang;Du-yun Ye
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文献类型：
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作者：
Dongxin Zhang;Yong-sheng Li;Hui Peng;Haojing Liu;Qiong Cheng;Xue Cheng;P. Zeng;Ping Wu;Hongxiang Chen;Yinping Huang;Du-yun Ye
胎盘炎症失调与许多妊娠并发症的发病机制有关。糖皮质激素（GCs）被普遍认为具有抗炎作用，在某些情况下也可以发挥促炎作用，而GCs是否以及如何促进胎盘炎症尚未得到深入研究。本文报道合成GC地塞米松（Dex）对大鼠胎盘炎症的相反调节作用。腹腔脂多糖（LPS）刺激1小时后皮下注射右美托咪唑，大鼠胎盘中中性粒细胞浸润和促炎il - 1b、il - 6和tnf的表达显著降低。相比之下，右美托咪唑预处理24小时可增强大鼠胎盘对LPS的促炎反应，并延迟炎症消退，这涉及到MAPKs和NF-kappaB的激活。从机械上看，右炔右酯预处理促进了5-脂氧合酶（ALOX5）的激活，增加了白三烯B4的产生，而通过下调ALOX15和ALOX15B的表达，抑制了大鼠胎盘中抗炎和促脂介质脂素A4 （LXA4）的生物合成。此外，在体内和体外，补充LXA4可以抑制dex增强的胎盘炎症，抑制dex介导的ALOX5激活。综上所述，这些发现表明，GCs暴露可以通过破坏LXA4的生物合成来促进胎盘炎症的发生和延迟消退。
ABSTRACT Inflammation dysregulation in placenta is implicated in the pathogenesis of numerous pregnancy complications. Glucocorticoids (GCs), universally considered anti-inflammatory, can also exert proinflammatory actions under some conditions, whereas whether and how GCs promote placental inflammation have not been intensively investigated. In this paper we report the opposing regulation of rat placental inflammation by synthetic GC dexamethasone (Dex). When Dex was subcutaneously injected 1 h after we administered an intraperitoneal lipopolysaccharide (LPS) challenge, neutrophil infiltration and proinflammatory Il1b, Il6, and Tnfa expression in rat placenta were significantly reduced. In contrast, Dex pretreatment for 24 h potentiated rat placental proinflammatory response to LPS and delayed inflammation resolution, which involved MAPKs and NF-kappaB activation. Mechanically, Dex pretreatment promoted 5-lipoxygenase (ALOX5) activation and increased leukotriene B4 production, whereas it inhibited the anti-inflammatory and proresolving lipid mediator lipoxin A4 (LXA4) biosynthesis in rat placenta via downregulating ALOX15 and ALOX15B expression. Moreover, LXA4 supplementation dampened Dex-potentiated placental inflammation and suppressed Dex-mediated ALOX5 activation in vivo and in vitro. Taken together, these findings suggest that GCs exposure could promote placental inflammation initiation and delay resolution via disrupting LXA4 biosynthesis.