The nuclear receptor Rev-erbalpha 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-erbalpha in the regulation of transcription pathways involving other nuclear receptors is emerging. Indeed, Rev-erbalpha 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 (RORalpha). Here, we show that Rev-erbalpha 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. LXRalpha binds to a specific response element in the human Rev-erbalpha promoter, thus inducing Rev-erbalpha transcriptional expression. Interestingly, Rev-erbalpha does not influence basal or LXR-regulated cholesterol homeostasis. However, Rev-erbalpha overexpression represses the induction of toll-like receptor (TLR)-4 by LXR agonists, whereas Rev-erbalpha 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-erbalpha 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-erbalpha as a new LXR target gene, inhibiting LXR-induction of TLR-4 in a negative transcriptional feedback loop, but not cholesterol homeostasis gene expression.
Fontaine
Coralie
C
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.
Rigamonti
Elena
E
Pourcet
Benoit
B
Duez
Hélène
H
Duhem
Christian
C
Fruchart
Jean-Charles
JC
Chinetti-Gbaguidi
Giulia
G
Staels
Bart
B
D001483:Base Sequence; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D019281:Dimerization; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D000071518:Liver X Receptors; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057093:Orphan Nuclear Receptors; D011485:Protein Binding / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; C064353:NR1D1 protein, human; C000605213:NR1H3 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D047490:Retinoid X Receptor alpha; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol