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

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.

• Authors: Shanshan Wu, Jihua Xue, Ying Yang, Haihong Zhu, Feng Chen, Jing Wang, Guohua Lou, Yanning Liu, Yixian Shi, Ye Yu, Caixia Xia, Ying Hu, Zhi Chen
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 37 Issue 2 Pg. 501-14 ( 2015) ISSN: 1421-9778 [Electronic] Germany
• PMID: 26315837 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 S. Karger AG, Basel.

Chemical References

• Chalcones
• Chemokines
• Enzyme Inhibitors
• Interferon-gamma
• isoliquiritigenin
• Protein Kinases

Topics

• Cell Line
• Cell Survival (drug effects)
• Chalcones (pharmacology)
• Chemokines (genetics, metabolism)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (drug effects)
• Gene Expression Regulation (drug effects)
• Hep G2 Cells
• Hepatocytes (cytology, drug effects, metabolism)
• Humans
• Interferon-gamma (pharmacology)
• Protein Kinases (genetics, metabolism)
• Signal Transduction (drug effects)