Helioxanthin inhibits interleukin-1β-induced MIP-1β production by reduction of c-jun expression and binding of the c-jun/CREB1 complex to the AP-1/CRE site of the MIP-1β promoter in Huh7 cells
| Autor: | Yueh-Hsiung Kuo, Sheau-Farn Yeh, Chen-Kung Chou, Damodar Janmanchi, Chih-Hsiu Lin, Hsing-Chih Hsu, Pei-Chi Tseng |
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| Rok vydání: | 2008 |
| Předmět: |
Pharmacology
Regulation of gene expression Messenger RNA biology Interleukin-1beta c-jun JNK Mitogen-Activated Protein Kinases Cyclic AMP Response Element-Binding Protein A Biochemistry Molecular biology Gene Expression Regulation Enzymologic Lignans Transcription Factor AP-1 Cell culture Cell Line Tumor Mitogen-activated protein kinase Gene expression biology.protein Humans Electrophoretic mobility shift assay Chemokine CCL4 Cyclic AMP Response Element-Binding Protein Promoter Regions Genetic Chromatin immunoprecipitation Protein Binding |
| Zdroj: | Biochemical Pharmacology. 76:1121-1133 |
| ISSN: | 0006-2952 |
| Popis: | An elevated level of macrophage inflammatory protein-1beta (MIP-1beta) induced by IL-1beta has been correlated with chronic hepatic inflammatory disease. However, molecular mechanism of IL-1beta-induced MIP-1beta expression in hepatic cells is obscure. Previously, we reported the mechanism of the anti-hepatitis B virus (HBV) activity of helioxanthin (HE-145). Here, we demonstrated that HE-145 inhibited IL-1beta-induced MIP-1beta expression in a dose-dependent manner in Huh7 cells. To understand the mode of action of HE-145, we first examined how IL-1beta induced MIP-1beta expression at the molecular level. Using selective inhibitors, we found that JNK and p38 pathways participated in IL-1beta-induced MIP-1beta expression. HE-145 specifically suppressed IL-1beta-induced c-jun mRNA and protein expression and prevented c-jun-mediated AP-1 DNA-binding activity, whereas it had no effect on IL-1beta-induced activation of JNK, p38 and ATF2. Further studies indicated that HE-145 may downregulate c-jun mRNA expression directly at transcriptional level without requirement of de novo protein synthesis. Mutational analysis and supershift assays indicated that IL-1beta stimulated c-jun and CREB1 binding to the essential AP-1/CRE site of the MIP-1beta promoter. The inhibitory effect of HE-145 on IL-1beta-induced MIP-1beta promoter activity was completely reversed by overexpressing c-jun. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay consistently revealed that HE-145 reduced c-jun binding to the AP-1/CRE site in vitro and in vivo. Our results established a major role for c-jun in IL-1beta-induced MIP-1beta expression in hepatic cells. The reduction in IL-1beta-induced c-jun expression and subsequent binding of the c-jun/CREB1 complex to AP-1/CRE site mainly contributed to the inhibitory action of HE-145 on IL-1beta-induced MIP-1beta production. |
| Databáze: | OpenAIRE |
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