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The Nuclear Receptor Rev-erb Is a Liver X Receptor (LXR) Target Gene Driving a Negative Feedback Loop on Select LXR-Induced Pathways in Human Macrophages

Institut Pasteur de Lille, and Institut National de la Santé et de la Recherche Médicale, Unité 545, Lille, F-59019 France; Université de Lille 2, Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de Médecine, Lille F-59006, France

Address all correspondence and requests for reprints to: Bart Staels, Institut National de la Santé et de la Recherche Médicale, Unité 545, Institut Pasteur de Lille, 1, rue du Professeur Calmette, Boite Postale 245, Lille 59019, France. E-mail: Bart.Staels{at}pasteur-lille.fr.

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

NURSA Molecule Pages Link:

Nuclear Receptors:   REV-ERBα  |  LXRα  |  RXRα

Ligands:   T0901317  |  GW 3965