Pregnane X receptor activation constrains mucosal NF-κB activity in active inflammatory bowel disease
Pregnane X receptor activation constrains mucosal NF-κB activity in active inflammatory bowel disease
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DOI：
10.1371/journal.pone.0221924
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发表时间：
2019-10-03
期刊：
影响因子：
3.7
通讯作者：
Peppelenbosch, Maikel
中科院分区：
文献类型：
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作者：
Deuring, J. Jasper;Li, Meng;Peppelenbosch, Maikel
孕烷X受体（Pregnane X Receptor，PXR）是粘膜对外源性应激反应的主要信号转导分子。众所周知，炎症性肠病伴随着外源性应激，但是PXR在限制炎症性肠病中的炎症反应中的重要性仍然模糊不清。结肠类器官和各种细胞培养模型（对于PXR是熟练的或遗传缺陷的）在体外用PXR配体利福平或媒介物。对NF-κ B活性的影响进行评估，通过测量白细胞介素-8（IL-8）和白细胞介素-1 β（IL-1 β）mRNA水平的qPCR和细胞培养模型NF-κ B的荧光素酶驱动的活性和蛋白质印迹信号transductionelements.ResultsWe观察结肠上皮PXR水平和NF-κ B的靶基因表达在克罗恩病患者的结肠活检之间的严格负相关。利福平激活的PXR是IBD中粘膜NF-κ B激活的限速因子。在肠类器官系统中也观察到结肠上皮PXR水平与NF-κ B靶基因表达之间的相关性。此外，在临床前在体外模型的肠道炎症，包括肠道类器官，基因失活的PXR释放NF-κ B依赖的信号转导，而相反NF-κ B B信号降低水平的PXR expressions.ConclusionsOur数据表明，PXR是一个主要的和临床相关的拮抗剂NF-κ B活性在肠上皮细胞室在炎症性肠病。
BackgroundThe Pregnane X Receptor (PXR) is a principal signal transducer in mucosal responses to xenobiotic stress. It is well-recognized that inflammatory bowel disease is accompanied by xenobiotic stress, but the importance of the PXR in limiting inflammatory responses in inflammatory bowel disease remains obscure at best.MethodsWe stimulate a total of 106 colonic biopsies from 19 Crohn's disease patients with active disease, 36 colonic biopsies from 8 control patients, colonic organoids and various cell culture models (either proficient or genetically deficient with respect to PXR) in vitro with the PXR ligand rifampicin or vehicle. Effects on NF-kappa B activity are assessed by measuring interleukin-8 (IL-8) and interleukin-1 beta (IL-1 beta) mRNA levels by qPCR and in cell culture models by NF-kappa B reporter-driven luciferase activity and Western blot for signal transduction elements.ResultsWe observe a strict inverse correlation between colonic epithelial PXR levels and NF-kappa B target gene expression in colonic biopsies from Crohn's disease patients. PXR, activated by rifampicin, is rate-limiting for mucosal NF-kappa B activation in IBD. The correlation between colonic epithelial PXR levels and NF-kappa B target gene expression was also observed in intestinal organoids system. Furthermore, in preclinical in vitro models of intestinal inflammation, including intestinal organoids, genetic inactivation of PXR unleashes NF-kappa B-dependent signal transduction whereas conversely NF-kappa B signaling reduces levels of PXR expression.ConclusionsOur data indicate that the PXR is a major and clinically relevant antagonist of NF-kappa B activity in the intestinal epithelial compartment during inflammatory bowel disease.