Liver anti-inflammatory pathways: Potential ways to control liver damage

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Liver

anti-inflammatory pathways: Potential ways to control liver damage

Fiona

J. Warner

Centenary

Institute, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia

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.

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