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

A role of the nuclear receptor Rev-erb alpha in the regulation of transcription pathways involving other nuclear receptors is emerging. Indeed, Rev-erb alpha 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 alpha (ROR alpha). Here, we show that Rev-erb alpha 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. LXR alpha binds to a specific response element in the human Rev-erb alpha promoter, thus inducing Rev-erb alpha transcriptional expression. Interestingly, Rev-erb alpha does not influence basal or LXR-regulated cholesterol homeostasis. However, Rev-erb alpha overexpression represses the induction of toll- like receptor (TLR)- 4 by LXR agonists, whereas Rev-erb alpha 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-erb alpha 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-erb alpha as a new LXR target gene, inhibiting LXR-induction of TLR-4 in a negative transcriptional feedback loop, but not cholesterol homeostasis gene expression.