异甘草素通过下调JAK1/STAT1、IRF3/MyD88、ERK/MAPK、JNK/MAPK和PI3K/Akt信号通路的激活来抑制肝细胞中干扰素-γ诱导基因的表达。
Isoliquiritigenin Inhibits Interferon-γ-Inducible Genes Expression in Hepatocytes through Down-Regulating Activation of JAK1/STAT1, IRF3/MyD88, ERK/MAPK, JNK/MAPK and PI3K/Akt Signaling Pathways.
作者信息
Wu Shanshan, Xue Jihua, Yang Ying, Zhu Haihong, Chen Feng, Wang Jing, Lou Guohua, Liu Yanning, Shi Yixian, Yu Ye, Xia Caixia, Hu Ying, Chen Zhi
机构信息
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China.
出版信息
Cell Physiol Biochem. 2015;37(2):501-14. doi: 10.1159/000430372. Epub 2015 Aug 28.
BACKGROUND & AIMS: The high expression levels of interferon-γ (IFN-γ)-inducible genes correlate positively with liver diseases. The present study aimed to explore the effect of isoliquiritigenin (ISL) on the expression of genes induced by IFN-γ in vitro, and to elucidate the underlying molecular mechanisms.
METHODS
HepG2 and L02 cells were divided into control, ISL, IFN-γ, and IFN-γ plus ISL groups. The cytotoxicity of compounds to cells was evaluated by Cell Counting Kit 8 (CCK8) assay; the expression levels of chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, CXCL11, and interleukin-6 (IL-6) in cells and supernatant were measured by quantitative real time polymerase chain reaction (qRT-PCR) and ELISA, respectively. Moreover, western blot was used to examine the phosphorylated levels of janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1), nuclear factor (NF)-κB, interferon regulatory factor 3 (IRF3)/myeloid differentiation factor 88 (MyD88), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Protein Kinase B (Akt) in HepG2 and L02 cells exposed to ISL, IFN-γ and IFN-γ plus ISL.
RESULTS
The results showed that IFN-γ treatment induced the expression of CXCL9, CXCL10, CXCL11, and IL-6 in HepG2 and LO2 cells, which could be significantly and dose-dependently inhibited by ISL treatment (P < 0.05 or P < 0.01), but the inhibitory effect of ISL on IL-6 expression was not so good as on CXCL9, CXCL10, and CXCL11 expression. Furthermore, ISL treatment dose-dependently inhibited the activation of JAK1/STAT1, IRF3/MyD88, extracellular signal-regulated kinase (ERK)/MAPK, c-Jun N-terminal kinase (JNK)/MAPK, and PI3K/Akt signaling pathways (P < 0.05), but had no effect on the activation of JAK2/STAT1, NF-κB and p38/MAPK signaling pathways.
CONCLUSION
We demonstrate that ISL inhibits IFN-γ-induced inflammation in hepatocytes via influencing the activation of JAK1/STAT1, IRF3/MyD88, ERK/MAPK, JNK/MAPK, and PI3K/Akt signaling pathways.
背景与目的
干扰素-γ（IFN-γ）诱导基因的高表达水平与肝脏疾病呈正相关。本研究旨在探讨异甘草素（ISL）对体外IFN-γ诱导基因表达的影响，并阐明其潜在的分子机制。
方法
将HepG2和L02细胞分为对照组、ISL组、IFN-γ组和IFN-γ加ISL组。采用细胞计数试剂盒8（CCK8）法评估化合物对细胞的细胞毒性；分别通过定量实时聚合酶链反应（qRT-PCR）和酶联免疫吸附测定（ELISA）检测细胞及上清液中趋化因子（C-X-C基序）配体9（CXCL9）、CXCL10、CXCL11和白细胞介素-6（IL-6）的表达水平。此外，采用蛋白质免疫印迹法检测暴露于ISL、IFN-γ和IFN-γ加ISL的HepG2和L02细胞中janus激酶（JAK）/信号转导子和转录激活子1（STAT1）、核因子（NF）-κB、干扰素调节因子3（IRF3）/髓样分化因子88（MyD88）、丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（Akt）的磷酸化水平。
结果
结果显示，IFN-γ处理可诱导HepG2和L02细胞中CXCL9、CXCL10.CXCL11和IL-6的表达，而ISL处理可显著且剂量依赖性地抑制其表达（P<0.05或P<0.01），但ISL对IL-6表达的抑制作用不如对CXCL9、CXCL10和CXCL11表达的抑制作用。此外，ISL处理剂量依赖性地抑制JAK1/STAT1、IRF3/MyD88、细胞外信号调节激酶（ERK）/MAPK、c-Jun氨基末端激酶（JNK）/MAPK和PI3K/Akt信号通路的激活（P<0.05），但对JAK2/STAT1、NF-κB和p38/MAPK信号通路的激活无影响。
结论
我们证明ISL通过影响JAK1/STAT1、IRF3/MyD88、ERK/MAPK、JNK/MAPK和PI3K/Akt信号通路的激活来抑制IFN-γ诱导的肝细胞炎症。
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