Venteclef N, Delerive P. Interleukin-1 receptor antagonist induction as an additional mechanism for liver receptor homolog-1 to negatively regulate the hepatic acute phase response. J Biol Chem 2007;282:4393–4399. (Reprinted with permission.)
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.
After trauma, infection, or acute inflammation, the liver participates in a program of modified gene expression collectively known as the acute phase response (APR). The main role of the APR is to limit tissue damage and to activate the innate immune response. A range of hepatic functions is altered during the APR, predominantly mediated by cytokine activation or suppression of target gene expression. The mechanisms for gene suppression in the injured/inflamed liver remain unknown, however, this suppression contributes to the negative APR. Among the principal hepatic physiological processes inhibited during the negative hepatic APR are genes involved in endobiotic/xenobiotic metabolism, glucose homeostasis, and bile formation. Cytokine, interleukin-1β (IL-1β), along with IL-6 are the main physiological mediators of the APR.
Venteclef and Delerive,1 scientists from GlaxoSmithKline in France, recently identified a role for the orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in suppressing the hepatic APR. LRH-1 is expressed in tissues derived from endoderm, including liver, intestine, and exocrine pancreas and is previously known to have distinct functions during mouse development and essential roles in cholesterol homeostasis.2 In mouse and human liver injury, hepatic LRH-1 is induced by tumor necrosis factor α.3 Transient transfection experiments and electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrate that LRH-1 reduces cytokine-mediated gene expression by blocking the activation of the transcription factor CCAAT/enhancer binding protein (C/EBP) and consequently represses the induction of the acute phase proteins haptoglobin (HP), serum amyloid A, and C-reactive protein in cultured hepatocytes. All these acute phase proteins have direct roles in the inflammatory process and are class I acute phase proteins responsive to IL-1β. Furthermore, LRH-1 does not affect the gene expression of plasminogen activator inhibitor-1, suggesting that LRH-1 selectively regulates cytokine-stimulated gene expression in hepatic cells.
This most recent work of Venteclef and Delerive further explores the anti-inflammatory role of LRH-1 and showed that in addition to negatively interfering with the development of the APR,4 LRH-1 also induces IL-1 receptor antagonist (IL-1RA), a naturally occurring anti-inflammatory protein that competitively blocks the binding of IL-1α and IL-1β to both type I and type II IL-1 receptors. LRH-1 regulates IL-1RA expression at the transcriptional level via binding to an LRH-1 response element as shown by promoter mapping and chromatin immunoprecipitation experiments. Furthermore, the contribution and relevance of LRH-1 induction and direct regulation of IL1-RA is demonstrated in heterozygous mice. The authors also note that the 2 events are time-dependent. Gene-silencing experiments revealed that IL-1RA induction contributes to the overall anti-inflammatory properties of LRH-1 after 24 hours but not after 6 hours of cytokine stimulation as seen with LRH-1 cytokine-mediated gene repression. LRH-1 first negatively regulates the APR by inhibiting C/EBP transcriptional activity and thereafter by inducing IL-1RA expression leading to IL-1 signaling blockade.
The identification and characterization of this anti-inflammatory hepatic response pathway introduces the paradigm of negative regulatory signals as part of a more general response aimed at controlling hepatic inflammation. Examples of other anti-inflammatory responses in the liver include CD200/CD200R interactions on macrophages,5 IL-10–producing hepatic CD8 T cells,6 and the μ-opioid receptor pathway.7 Overall, knowledge of such ligand and signaling pathways, including those that modulate LRH-1 activity, combined with a determination of their roles in normal and diseased liver, may lead to potential new therapeutic targets aimed at controlling the hepatic inflammatory response.