Oxysterols exert proinflammatory effects in placental trophoblasts via TLR4-dependent, cholesterol-sensitive activation of NF-κB
Oxysterols exert proinflammatory effects in placental trophoblasts via TLR4-dependent, cholesterol-sensitive activation of NF-κB
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DOI：
10.1093/molehr/gas001
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发表时间：
2012-07-01
影响因子：
4
通讯作者：
Keelan, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Aye, Irving L. M. H.;Waddell, Brendan J.;Keelan, Jeffrey A.
氧化胆固醇代谢物（氧化固醇）促进多种细胞类型的炎症，并被认为参与许多疾病病理。氧固醇浓度在怀孕期间增加，同时伴有全身氧化应激和炎症。我们检验了氧化固醇25-羟基胆固醇（25-OHC）和7-酮胆固醇（7-ketoC）促进胎盘滋养层炎症的假设，并确定了相关机制。用25-OHC和7-ketoC处理培养的原代滋养层细胞，以浓度依赖性方式增加促炎细胞因子（白细胞介素-6、巨噬细胞炎性蛋白-1和肿瘤坏死因子-）的产生。使用选择性TLR 4复合物形成抑制剂（OxPAPC）或信号传导抑制剂（CLI 095）抑制TLR 4活化可预防脂多糖（LPS）和氧固醇诱导的炎性细胞因子产生。用I-kB激酶活性的选择性抑制剂（孤雌菊和TPCA-1）预处理滋养层细胞减少了氧化固醇和LPS刺激的炎症反应，这与TLR 4信号传导下游的核因子κ B（NF-B）通路的参与一致。这两种氧固醇也增加了NF-B亚基p65/RelA的磷酸化和核定位。还已知氧固醇激活肝脏X受体（LXR），其可以直接或间接地通过膜胆固醇减少来抑制炎症信号传导。用LXR激动剂T0901317治疗，产生显著的抗炎作用，减少LPS和氧固醇驱动的细胞因子产生。用甲基-β-环糊精处理以消耗膜微区胆固醇，从而破坏TLR 4信号传导，同样消除了它们的作用。总之，这些发现表明，尽管氧固醇可能激活胎盘中的促炎和抗炎途径，但主要作用是通过TLR 4依赖性激活NF-B促进胎盘炎症。
Oxidized cholesterol metabolites (oxysterols) promote inflammation in a variety of cell types and are thought to be involved in a number of disease pathologies. Oxysterol concentrations are increased in pregnancy, together with systemic oxidative stress and inflammation. We tested the hypothesis that oxysterols 25-hydroxycholesterol (25-OHC) and 7-ketocholesterol (7-ketoC) promote placental trophoblast inflammation, and determined the mechanisms involved. Treatment of primary trophoblasts in culture with 25-OHC and 7-ketoC increased the production of proinflammatory cytokines (interleukin-6, macrophage inflammatory protein-1 and tumour necrosis factor-) in a concentration-dependent fashion. Inhibition of TLR4 activation using selective inhibitors of TLR4 complex formation (OxPAPC) or signalling transmission (CLI095) prevented lipopolysaccharide (LPS)- and oxysterol-induced inflammatory cytokine production. Pretreatment of trophoblasts with selective inhibitors of I-kB kinase activity (parthenolide and TPCA-1) reduced oxysterol- and LPS-stimulated inflammatory responses, consistent with the involvement of the nuclear factor kappa B (NF-B) pathway downstream of TLR4 signalling. Both oxysterols also increased the phosphorylation and nuclear localization of NF-B subunit p65/RelA. Oxysterols are also known to activate liver X receptors (LXRs) which can inhibit inflammatory signalling, either directly or indirectly via membrane cholesterol reduction. Treatment with the LXR agonist, T0901317, exerted significant anti-inflammatory effects, reducing LPS- and oxysterol-driven cytokine production. Treatment with methyl--cyclodextrin to deplete membrane microdomain cholesterol and thereby disrupt TLR4 signalling, similarly abrogated their effects. Together, these findings indicate that although oxysterols likely activate both pro- and anti-inflammatory pathways in the placenta, the predominant effect is the promotion of placental inflammation via TLR4-dependent activation of NF-B.