It is now evident that many nuclear hormone receptors can modulate target gene expression. REV-ERB
, one of the nuclear hormone receptors with the capacity to alter clock function, is critically involved in lipid metabolism, adipogenesis, and the inflammatory response. Recent studies suggest that REV-ERB plays a key role in the mediation between clockwork and inflammation. The purpose of the current study was to investigate the role of REV-ERB in the regulation of interleukin-6( il6) gene expression in murine macrophages. REV-ERB agonists, or overexpression of rev-erbin the murine macrophage cell line RAW264 cells, suppressed the induction of il6mRNA following a lipopolysaccharide (LPS) endotoxin challenge. Also, rev-erboverexpression decreased LPS-stimulated nuclear factor B (NF B) activation in RAW264 cells. We showed that REV-ERB represses il6expression not only indirectly through an NF B binding motif but also directly through a REV-ERB binding motif in the murine il6promoter region. Furthermore, peritoneal macrophages from mice lacking rev-erbincreased il6mRNA expression. These data suggest that REV-ERB regulates the inflammatory response of macrophages through the suppression of il6expression. REV-ERB may therefore be identified as a potent anti-inflammatory receptor and be a therapeutic target receptor of inflammatory diseases.