Liggins Institute, University of Auckland, Auckland, New Zealand.
Br J Pharmacol. 2010 Aug;160(7):1808-22. doi: 10.1111/j.1476-5381.2010.00839.x.
Inflammation of the extraplacental membranes plays a key role in the pathogenesis of preterm labour. The aim of this study was to screen a number of commercially available small molecule nuclear factor-kappa B inhibitors to identify candidates suitable for clinical evaluation as anti-inflammatory agents for the prevention of preterm birth.
Nine inhibitors were evaluated across a range of concentrations for their ability to inhibit lipopolysaccharide (LPS)-stimulated cytokine production in primary term choriodecidual cells in culture without affecting cell viability. Expression of 112 inflammation- and apoptosis-related genes was evaluated using boutique oligonucleotide arrays.
Two IKKbeta inhibitors were found to be highly effective and non-toxic inhibitors of choriodecidual cytokine production: parthenolide and [5-(p-fluorophenyl)-2-ureido] thiophene-3-carboxamide (TPCA-1). Both compounds also inhibited LPS-stimulated nuclear translocation of p65/RelA. Expression of 38 genes on the arrays (34%) was significantly (P < 0.05) inhibited by TPCA-1 or parthenolide. Of the 14 genes significantly stimulated by LPS, all were inhibited by TPCA-1 and 12 were inhibited by parthenolide. Overall, gene expression was more robustly inhibited by TPCA-1 than parthenolide; however, expression of two genes was only inhibited by parthenolide. Neither compound significantly altered the expression profile of anti-apoptosis genes on the arrays.
These studies provide evidence that pharmacological inhibition of IKKbeta activity holds promise as a potential strategy for the prevention and/or treatment of inflammation-driven preterm birth. TPCA-1 appeared the most promising compound among those tested in this study. Different inhibitors may have subtly different effect profiles despite having similar modes of action.
胎盘外膜的炎症在早产的发病机制中起着关键作用。本研究的目的是筛选一些市售的小分子核因子-κB 抑制剂，以鉴定适合临床评估的候选药物，作为预防早产的抗炎药物。
在体外培养的足月绒毛膜蜕膜细胞中，评估 9 种抑制剂在不同浓度下抑制脂多糖（LPS）刺激细胞因子产生的能力，同时不影响细胞活力。使用 boutique 寡核苷酸阵列评估 112 种与炎症和细胞凋亡相关的基因表达。
发现两种 IKKβ抑制剂对绒毛膜蜕膜细胞因子的产生具有高度有效的非毒性抑制作用：小白菊内酯和[5-（对氟苯基）-2-脲基]噻吩-3-甲酰胺（TPCA-1）。这两种化合物也抑制了 LPS 刺激的 p65/RelA 核转位。在芯片上的 38 个基因（34%）的表达明显（P < 0.05）被 TPCA-1 或小白菊内酯抑制。在 LPS 显著刺激的 14 个基因中，所有基因均被 TPCA-1 抑制，12 个基因被小白菊内酯抑制。总的来说，TPCA-1 对基因表达的抑制作用比小白菊内酯更强；然而，只有小白菊内酯抑制了两个基因的表达。这两种化合物都没有显著改变芯片上抗凋亡基因的表达谱。
这些研究为抑制 IKKβ 活性提供了药理学治疗早产的潜在策略的证据。在本研究中测试的化合物中，TPCA-1 似乎是最有前途的化合物。尽管具有相似的作用机制，但不同的抑制剂可能具有略有不同的作用谱。
