Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus.
Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus.
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DOI：
10.2147/jir.s32108
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发表时间：
2012
影响因子：
4.5
通讯作者：
Belkacemi L
中科院分区：
文献类型：
--
作者：
Boles JL;Ross MG;Beloosesky R;Desai M;Belkacemi L
脑瘫是一种非进行性运动障碍综合征，目前尚无有效的治疗方法。大多数脑瘫病例的病因仍然未知，然而，最近的流行病学数据表明胎儿神经损伤和感染/炎症之间存在关联。母体感染/炎症可能与胎盘细胞因子的诱导相关，这可能导致胎儿促炎细胞因子暴露增加，并发生新生儿神经损伤。因此，我们试图探索母体感染可能产生胎盘炎症反应的机制。我们专门研究了早产和近足月胎龄大鼠胎盘细胞因子的产生和Toll样受体4（TLR 4）通路的激活对脂多糖暴露的反应。用0、1或10 μg/mL脂多糖处理妊娠大鼠的早产（e16）或近足月（e20）胎盘外植体。通过乳酸脱氢酶测定评估外植体完整性。使用酶联免疫吸附测定试剂盒测定白细胞介素-6和肿瘤坏死因子α水平。Western blot检测TLR 4和活化B细胞磷酸化核因子κ轻链增强子（NFκB）蛋白表达水平。在e16和e20，乳酸脱氢酶水平与脂多糖治疗无变化。暴露于脂多糖后，从e16胎盘外植体释放的白细胞介素-6和肿瘤坏死因子α分别增加了4倍和8-9倍（与载体相比P < 0.05）。相反，与载体相比，从e20外植体释放的白细胞介素-6没有显著差异，并且在暴露于脂多糖后，肿瘤坏死α释放仅高出2倍（P < 0.05相对于载体）。在e16和e20暴露于脂多糖的胎盘外植体的核组分中，磷酸化NFκB蛋白表达显著增加，尽管TLR 4蛋白表达不受影响。与e20相比，在e16，脂多糖诱导更高的白细胞介素-6和肿瘤坏死因子α表达，这表明早产胎盘可能对脂多糖感染有更大的胎盘细胞因子反应。此外，增加的磷酸化NFκB表明胎盘细胞因子诱导可能通过激活TLR 4途径发生。
Cerebral palsy is a nonprogressive motor impairment syndrome that has no effective cure. The etiology of most cases of cerebral palsy remains unknown; however, recent epidemiologic data have demonstrated an association between fetal neurologic injury and infection/inflammation. Maternal infection/inflammation may be associated with the induction of placental cytokines that could result in increased fetal proinflammatory cytokine exposure, and development of neonatal neurologic injury. Therefore, we sought to explore the mechanism by which maternal infection may produce a placental inflammatory response. We specifically examined rat placental cytokine production and activation of the Toll-like receptor 4 (TLR4) pathway in response to lipopolysaccharide exposure at preterm and near-term gestational ages. Preterm (e16) or near-term (e20) placental explants from pregnant rats were treated with 0, 1, or 10 μg/mL lipopolysaccharide. Explant integrity was assessed by lactate dehydrogenase assay. Interleukin-6 and tumor necrosis alpha levels were determined using enzyme-linked immunosorbent assay kits. TLR4 and phosphorylated nuclear factor kappa light chain enhancer of activated B cells (NFκB) protein expression levels were determined by Western blot analysis. At both e16 and e20, lactate dehydrogenase levels were unchanged by treatment with lipopolysaccharide. After exposure to lipopolysaccharide, the release of interleukin-6 and tumor necrosis alpha from e16 placental explants increased by 4-fold and 8–9-fold, respectively (P < 0.05 versus vehicle). Conversely, interleukin-6 release from e20 explants was not significantly different compared with vehicle, and tumor necrosis alpha release was only 2-fold higher (P < 0.05 versus vehicle) following exposure to lipopolysaccharide. Phosphorylated NFκB protein expression was significantly increased in the nuclear fraction from placental explants exposed to lipopolysaccharide at both e16 and e20, although TLR4 protein expression was unaffected. Lipopolysaccharide induces higher interleukin-6 and tumor necrosis alpha expression at e16 versus e20, suggesting that preterm placentas may have a greater placental cytokine response to lipopolysaccharide infection. Furthermore, increased phosphorylated NFκB indicates that placental cytokine induction may occur by activation of the TLR4 pathway.