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PXR Functionally Interacts with NF-κB and AP-1 to Downregulate the Inflammation-Induced Expression of Chemokine CXCL2 in Mice
Cells ( IF 5.1 ) Pub Date : 2020-10-15 , DOI: 10.3390/cells9102296
Maya Okamura , Ryota Shizu , Taiki Abe , Susumu Kodama , Takuomi Hosaka , Takamitsu Sasaki , Kouichi Yoshinari

Pregnane X receptor (PXR) is a liver-enriched xenobiotic-responsive transcription factor. Although recent studies suggest that PXR shows anti-inflammatory effects by suppressing nuclear factor kappa B (NF-κB), the detailed mechanism remains unclear. In this study, we aimed to elucidate this mechanism. Mice were treated intraperitoneally with the PXR agonist pregnenolone 16α-carbonitrile (PCN) and/or carbon tetrachloride (CCl4). Liver injury was evaluated, and hepatic mRNA levels were determined via quantitative reverse transcription polymerase chain reaction. Reporter assays with wild-type and mutated mouse Cxcl2 promoter-containing reporter plasmids were conducted in 293T cells. Results showed that the hepatic expression of inflammation-related genes was upregulated in CCl4-treated mice, and PCN treatment repressed the induced expression of chemokine-encoding Ccl2 and Cxcl2 among the genes investigated. Consistently, PCN treatment suppressed the increased plasma transaminase activity and neutrophil infiltration in the liver. In reporter assays, tumor necrosis factor-α-induced Cxcl2 expression was suppressed by PXR. Although an NF-κB inhibitor or the mutation of an NF-κB-binding motif partly reduced PXR-dependent suppression, the mutation of both NF-κB and activator protein 1 (AP-1) sites abolished it. Consistently, AP-1-dependent gene transcription was suppressed by PXR with a construct containing AP-1 binding motifs. In conclusion, the present results suggest that PXR exerts anti-inflammatory effects by suppressing both NF-κB- and AP-1-dependent chemokine expression in mouse liver.

中文翻译:

PXR在功能上与NF-κB和AP-1相互作用,以下调炎症诱导的趋化因子CXCL2在小鼠中的表达。

孕烷X受体(PXR)是一种富含肝脏的异生物素响应转录因子。尽管最近的研究表明PXR通过抑制核因子κB(NF-κB)表现出抗炎作用,但其详细机制仍不清楚。在这项研究中,我们旨在阐明这种机制。用PXR激动剂孕烯醇酮16α-腈(PCN)和/或四氯化碳(CCl 4)腹膜内治疗小鼠。评价肝损伤,并通过定量逆转录聚合酶链反应测定肝mRNA水平。在293T细胞中使用野生型和突变的含小鼠Cxcl2启动子的报告基因进行报告基因分析。结果表明,炎症相关基因的肝表达在CCl中上调用4处理的小鼠和PCN处理抑制了所研究基因中编码趋化因子的Ccl2Cxcl2的诱导表达。一致地,PCN治疗抑制了血浆中转氨酶活性的增加和肝脏中性粒细胞的浸润。在报告基因检测中,肿瘤坏死因子-α诱导的Cxcl2PXR抑制表达。尽管NF-κB抑制剂或NF-κB结合基序的突变部分降低了PXR依赖性抑制,但NF-κB和激活蛋白1(AP-1)位点的突变均消除了它。一致地,PXR用含有AP-1结合基序的构建体抑制了AP-1依赖的基因转录。总之,目前的结果表明,PXR通过抑制小鼠肝脏中NF-κB-和AP-1依赖性趋化因子的表达发挥抗炎作用。
更新日期:2020-10-15
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