title: 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.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Shanshan
authors: S
authors: Wu
authors: Jihua
authors: J
authors: Xue
authors: Ying
authors: Y
authors: Yang
authors: Haihong
authors: H
authors: Zhu
authors: Feng
authors: F
authors: Chen
authors: Jing
authors: J
authors: Wang
authors: Guohua
authors: G
authors: Lou
authors: Yanning
authors: Y
authors: Liu
authors: Yixian
authors: Y
authors: Shi
authors: Ye
authors: Y
authors: Yu
authors: Caixia
authors: C
authors: Xia
authors: Ying
authors: Y
authors: Hu
authors: Zhi
authors: Z
authors: Chen
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047188:Chalcones; D018925:Chemokines; D004791:Enzyme Inhibitors; D007371:Interferon-gamma; C040920:isoliquiritigenin; D011494:Protein Kinases