Kodama Susumu, Shimura Takuto, Kuribayashi Hideaki, Abe Taiki, Yoshinari Kouichi
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Miyagi 980-8578, Japan; Laboratory of Pharmacotherapy of Life-Style Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Toxicol Lett. 2017 Apr 5;271:58-65. doi: 10.1016/j.toxlet.2017.02.018. Epub 2017 Feb 22.
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 anti-inflammatory effect of pregnenolone 16α-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.
孕烷X受体（PXR）作为药物/外源性物质清除的关键调节因子而广为人知。在被配体激活后，PXR通过转录上调药物代谢酶和药物转运体的表达。最近的研究表明，PXR在调节免疫/炎症反应中也发挥作用。包括合成配体和植物化学物质在内的特定PXR激活剂已被证明可改善小鼠化学诱导的结肠炎。在本研究中，我们使用野生型和Pxr基因敲除小鼠，研究了啮齿动物PXR的典型激活剂孕烯醇酮16α-腈（PCN）在刀豆蛋白A（Con A）诱导的肝损伤（一种免疫介导的肝损伤模型）中的抗炎作用。出乎意料的是，PCN预处理不仅能显著改善野生型小鼠，也能改善Pxr基因敲除小鼠的Con A诱导的肝损伤，同时伴有血浆ALT水平降低和组织学改善。发现在Con A诱导的肝损伤早期，PCN预处理能显著抑制野生型和Pxr基因敲除小鼠肝脏中Cxcl2和Ccl2 mRNA表达的诱导以及中性粒细胞浸润。我们的结果表明，PCN具有独立于PXR激活的意外免疫抑制活性，可保护小鼠免受Con A诱导的免疫介导的肝损伤。
