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Interleukin-1 receptor antagonist induction as an additional mechanism for liver receptor homolog-1 to negatively regulate the hepatic acute phase response.

Abstract
The liver receptor homolog-1 (LRH-1) is an orphan nuclear receptor believed to play a key role in bile acid metabolism, cholesterol homeostasis, and intestinal cell crypt renewal. LRH-1 has recently been reported to negatively regulate the hepatic acute phase response by antagonizing, at least in part, the CCAAT/enhancer-binding protein signaling pathway. Here we have shown, using adenovirus-mediated LRH-1 overexpression and gene-silencing experiments, that the interleukin-1 receptor antagonist (IL-1RA) gene is a novel LRH-1 target gene in hepatic cells. Promoter mapping and chromatin immunoprecipitation experiments revealed that LRH-1 regulates IL-1RA gene expression under inflammatory conditions at the transcriptional level via the binding to an LRH-1 response element. Interestingly, IL-1RA induction by an intraperitoneal injection of lipopolysaccharide is significantly lower in LRH-1 heterozygous compared with wild-type mice, demonstrating the contribution of LRH-1 in IL-1RA gene regulation. Finally, RNA interference experiments indicate that LRH-1 blocks the hepatic acute phase response by, at least in part, inducing IL-1RA expression. Taken together, these results lead to the identification of IL-1RA as a novel LRH-1 target gene and demonstrate the existence of multiple mechanisms contributing to the overall anti-inflammatory properties of LRH-1 in hepatic cells.
AuthorsNicolas Venteclef, Philippe Delerive
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 7 Pg. 4393-4399 (Feb 16 2007) ISSN: 0021-9258 [Print] United States
PMID17158876 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • CCAAT-Binding Factor
  • DNA-Binding Proteins
  • Interleukin 1 Receptor Antagonist Protein
  • Lipopolysaccharides
  • NR5A2 protein, human
  • Nr5a2 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
Topics
  • Acute-Phase Reaction (chemically induced, metabolism)
  • Adenoviridae
  • Animals
  • CCAAT-Binding Factor (metabolism)
  • Cell Line, Tumor
  • DNA-Binding Proteins (genetics, metabolism)
  • Female
  • Gene Expression Regulation (drug effects)
  • Gene Silencing
  • Humans
  • Interleukin 1 Receptor Antagonist Protein (biosynthesis, genetics)
  • Lipopolysaccharides (toxicity)
  • Liver (metabolism)
  • Mice
  • Promoter Regions, Genetic
  • Receptors, Cytoplasmic and Nuclear (genetics, metabolism)
  • Signal Transduction (drug effects)
  • Transcription Factors (genetics, metabolism)
  • Transcription, Genetic (drug effects)

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