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.