PMID:12524534

Citation	Joseph, SB, Castrillo, A, Laffitte, BA, Mangelsdorf, DJ and Tontonoz, P (2003) Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat. Med. 9:213-9
Abstract	Macrophages have important roles in both lipid metabolism and inflammation and are central to the pathogenesis of atherosclerosis. The liver X receptors (LXRs) are established mediators of lipid-inducible gene expression, but their role in inflammation and immunity is unknown. We demonstrate here that LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Transcriptional profiling of lipopolysaccharide (LPS)-induced macrophages reveals reciprocal LXR-dependent regulation of genes involved in lipid metabolism and the innate immune response. In vitro, LXR ligands inhibit the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase (COX)-2 and interleukin-6 (IL-6) in response to bacterial infection or LPS stimulation. In vivo, LXR agonists reduce inflammation in a model of contact dermatitis and inhibit inflammatory gene expression in the aortas of atherosclerotic mice. These findings identify LXRs as lipid-dependent regulators of inflammatory gene expression that may serve to link lipid metabolism and immune functions in macrophages.
Links	PubMed Online version:10.1038/nm820
Keywords	Animals; Cells, Cultured; Inflammation/physiopathology; Lipids/physiology; Lipopolysaccharides/pharmacology; Mice; NF-kappa B/metabolism; Nitric Oxide Synthase/antagonists & inhibitors; Nitric Oxide Synthase/biosynthesis; Nitric Oxide Synthase Type II; Receptors, Cytoplasmic and Nuclear/agonists; Receptors, Cytoplasmic and Nuclear/physiology; Signal Transduction
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:NR1H3		GO:0032720: negative regulation of tumor necrosis factor production	ECO:0000316:	UniProtKB:Q60644	P		Figure 6a This figure shows that in Nr1h3–/–Nr1h2–/– (DKO) mice the expression of TNF-α was enhanced in response to LPS in vivo indicating that Nr1H2 is an inhibitor of TNF. The expression was determined using RT-PCR.	complete
MOUSE:NR1H3		GO:0045824: negative regulation of innate immune response	ECO:0000314:		P		Figure 1: This figure shows that NR1H3 inhibits macrophage responses to bacterial infections. Each part of this figure shows that iNOS and nitrate are inhibited by NR1H3 in different conditions during infection. iNOS and nitrate are important in innate immunity for anti-microbial and anti-tumor activities as well as the oxidative burst of macrophages.	complete
MOUSE:NR1H3		GO:0050728: negative regulation of inflammatory response	ECO:0000315:		P		Figure 3: This figure is a DNA microarray showing the effect of NR1H3 on LPS-induced gene expression in macrophages. Based on changes in gene expression between WT-mice and KO-mice NR1H2 inhibits genes involved in inflammation. In the WT-mice these genes are inhibited, in KO- NR1H2 and KO- NR1H3 mice these genes are partially inhibited, and in DKO mice these genes are not inhibited.	complete
MOUSE:NR1H3		GO:0043620: regulation of transcription in response to stress	ECO:0000314:		P		Figure 5: LXRs antagonize the action of NF-κB on the iNOS and COX-2 promoters. Fig.5a,b,c: Activation of LXRα/RXRα and LXRβ/RXRα inhibits the induction of iNOS and COX-2 gene promoters by LPS and inhibits expression of the reporter containing multiple NF-κB binding sites. Fig.5e,f: The inhibitory effect of LXR on COX-2 promoters is lost when NF-κB activity was blocked by transfection of a dominant-negative IKK or its binding sites mutated.	complete

References

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