Decreased Pregnane X Receptor Expression in Children with Active Crohn's Disease.
Decreased Pregnane X Receptor Expression in Children with Active Crohn's Disease.
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DOI：
10.1124/dmd.115.068742
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Leeder JS
中科院分区：
文献类型：
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作者：
Shakhnovich V;Vyhlidal C;Friesen C;Hildreth A;Singh V;Daniel J;Kearns GL;Leeder JS
据报道，在炎症性肠病（IBD）的动物模型中，胆甾烷X受体（PXR）的表达降低。为了研究PXR在患有克罗恩病（一种IBD）的儿童中的差异表达，从来自18名患有克罗恩病（CD）的儿童和12名年龄和性别匹配的对照（7- 17岁）的存档肠活检中提取RNA。本研究的目的是比较PXR，细胞色素p450 3A 4（CYP 3A 4）和绒毛蛋白1（VIL 1）（上皮细胞完整性的标志物）的相对mRNA表达在炎症末端回肠（TI）与非炎症十二指肠CD儿童。通过逆转录实时定量聚合酶链反应测定相对表达，将数据标准化为甘油醛3-磷酸脱氢酶，并通过配对t检验探索基因表达的差异。在CD患者中，与非炎症十二指肠相比，炎症十二指肠中的PXR表达降低（TI = 1.88 ± 0.89，十二指肠= 2.5 ± 0.67; P < 0.001），但对照组中的PXR表达没有降低（TI = 2.11 ± 0.41，十二指肠= 2.26 ± 0.61; P = 0.52）。CD中CYP 3A 4表达降低（TI = -0.89 ± 3.11 vs.十二指肠= 1.90 ± 2.29; P < 0.05），但对照组无差异（TI = 2.46 ± 0.51 vs十二指肠= 2.60 ± 0.60; P = 0.61），VIL 1也是如此（CD TI = 3.80 ± 0.94与十二指肠= 4.61 ± 0.52; P < 0.001;对照TI = 4.30 ± 0.35与十二指肠= 4.47 ± 0.40; P = 0.29）。PXR表达与VIL 1（r = 0.78，P = 0.01）和CYP 3A 4（r = 0.52，P = 0.01）表达相关。总之，PXR，CYP 3A 4和VIL 1的表达下降，只有在积极发炎的小肠组织的儿童CD。我们的研究结果表明，炎症有可能影响基因的表达，并可能影响肠道蛋白质的表达，这对药物的处置和反应很重要。所观察到的基因表达差异模式支持进一步研究PXR在小儿克罗恩病发病机制和/或治疗中的作用。
Expression of the pregnane X receptor (PXR) has been reported to be decreased in animal models of inflammatory bowel disease (IBD). To investigate the differential expression of PXR in children with Crohn’s disease, a type of IBD, RNA was extracted from archived intestinal biopsies from 18 children with Crohn’s disease (CD) and 12 age- and sex-matched controls (aged 7–17yrs). The aim of this investigation was to compare the relative mRNA expression of PXR, cytochrome p450 3A4 (CYP3A4), and villin 1 (VIL1) (a marker of epithelial cell integrity) in the inflamed terminal ileum (TI) versus noninflamed duodenum of children with CD. Relative expression was determined via reverse transcription real-time quantitative polymerase chain reaction, data normalized to glyceraldehyde 3-phosphate dehydrogenase, and differences in gene expression explored via paired t tests. PXR expression was decreased in the inflamed TI versus noninflamed duodenum (TI = 1.88 ± 0.89 versus duodenum = 2.5 ± 0.67; P < 0.001) in CD, but not controls (TI = 2.11 ± 0.41 versus duodenum = 2.26 ± 0.61; P = 0.52). CYP3A4 expression was decreased in CD (TI = –0.89 ± 3.11 versus duodenum = 1.90 ± 2.29; P < 0.05), but not controls (TI = 2.46 ± 0.51 versus duodenum = 2.60 ± 0.60; P = 0.61), as was VIL1 (CD TI = 3.80 ± 0.94 versus duodenum = 4.61 ± 0.52; P < 0.001; controls TI = 4.30 ± 0.35 versus duodenum = 4.47 ± 0.40; P = 0.29). PXR expression correlated with VIL1 (r = 0.78, P = 0.01) and CYP3A4 (r = 0.52, P = 0.01) expression. In conclusion, PXR, CYP3A4, and VIL1 expression was decreased only in the actively inflamed small intestinal tissue in children with CD. Our findings suggest that inflammation has the potential to influence expression of genes, and potentially intestinal proteins, important to drug disposition and response. The observed differential patterns of gene expression support further investigation of the role of PXR in the pathogenesis and/or treatment of pediatric Crohn’s disease.