The nuclear receptor Rev-erbα is a Liver X Receptor (LXR) target gene driving a negative feedback loop on select LXR-induced pathways in human macrophages

Abstract

A role of the nuclear receptor Rev-erbα in the regulation of transcription pathways involving other nuclear receptors is emerging. Indeed, Rev-erbα is a negative regulator of transcription by binding to overlapping response elements shared with various nuclear receptors, including the peroxisome proliferator-activated receptors and the retinoid-related orphan receptor α (RORα). Here, we show that Rev-erbα is expressed in primary human macrophages and that its expression is induced by synthetic ligands for the liver X receptors (LXRs), which control cholesterol homeostasis, inflammation, and the immune response in macrophages. LXRα binds to a specific response element in the human Rev-erbα promoter, thus inducing Rev-erbα transcriptional expression. Interestingly, Rev-erbα does not influence basal or LXR-regulated cholesterol homeostasis. However, Rev-erbα overexpression represses the induction of toll-like receptor (TLR)-4 by LXR agonists, whereas Rev-erbα silencing by short interfering RNA results in enhanced TLR-4 expression upon LXR activation. Electrophoretic mobility shift, chromatin immunoprecipitation, and transient transfection experiments demonstrate that Rev-erbα represses human TLR-4 promoter activity by binding as a monomer to a RevRE site overlapping with the LXR response element site in the TLR-4 promoter. These data identify Rev-erbα as a new LXR target gene, inhibiting LXR-induction of TLR-4 in a negative transcriptional feedback loop, but not choles-terol homeostasis gene expression. Copyright © 2008 by The Endocrine Society.