Pregnenolone 16α-carbonitrile ameliorates concanavalin A-induced liver injury in mice independent of the nuclear receptor PXR activation
Pregnenolone 16α-carbonitrile ameliorates concanavalin A-induced liver injury in mice independent of the nuclear receptor PXR activation
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DOI：
10.1016/j.toxlet.2017.02.018
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发表时间：
2017-04-05
影响因子：
3.5
通讯作者：
Yoshinari, Kouichi
中科院分区：
文献类型：
--
作者：
Kodama, Susumu;Shimura, Takuto;Yoshinari, Kouichi
众所周知，甾烷X受体（PXR）是药物/异生物质清除的关键调节因子。在配体激活后，PXR转录上调药物代谢酶和药物转运蛋白的表达。最近的研究表明，PXR还在调节免疫/炎症反应中发挥作用。特异性PXR激活剂，包括合成配体和植物化学物质，已被证明可以改善小鼠中化学诱导的结肠炎。在这项研究中，我们使用野生型和Pxr（/）小鼠研究了双烯醇酮16 α-甲腈（PCN）（啮齿动物PXR的原型激活剂）在刀豆球蛋白A（Con A）诱导的肝损伤（免疫介导的肝损伤模型）中的抑制作用。出乎意料的是，PCN预处理不仅显著改善了野生型小鼠的Con A诱导的肝损伤，而且还显著改善了Pxr（/）小鼠的肝损伤，并伴有血浆ALT水平降低和组织学改善。在ConA诱导的肝损伤的早期时间点，发现用PCN预处理显著抑制野生型和Pxr（/）小鼠肝中Cxcl 2和Ccl 2 mRNA表达的诱导以及中性粒细胞浸润。我们的研究结果表明，PCN具有意想不到的免疫抑制活性，不依赖于PXR激活，以保护小鼠免受Con A诱导的免疫介导的肝损伤。(C)2017爱思唯尔B. V.保留所有权利。
The pregnane X receptor (PXR) is well-known as a key regulator of drug/xenobiotic clearance. Upon activation by ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters. Recent studies have revealed that PXR also plays a role in regulating immune/inflammatory responses. Specific PXR activators, including synthetic ligands and phytochemicals, have been shown to ameliorate chemically induced colitis in mice. In this study, we investigated an antiinflammatory effect of pregnenolone 16 alpha-carbonitrile (PCN), a prototypical activator for rodent PXR, in concanavalin A (Con A)-induced liver injury, a model of immune-mediated liver injury, using wild-type and Pxr (/) mice. Unexpectedly, pretreatment with PCN significantly ameliorated Con A-induced liver injury in not only wild-type but Pxr (/) mice as well, accompanied with lowered plasma ALT levels and histological improvements. Pretreatment with PCN was found to significantly repress the induction of Cxcl2 and Ccl2 mRNA expression and neutrophil infiltration into the liver of both wild-type and Pxr (/) mice at the early time point of Con A- induced liver injury. Our results indicate that PCN has unexpected immunosuppressive activity independent of PXR activation to protect mice from immune- mediated liver injury induced by Con A. (C) 2017 Elsevier B.V. All rights reserved.