Direct and indirect suppression of interleukin-6 gene expression in murine macrophages by nuclear orphan receptor REV-ERB α

It is now evident that many nuclear hormone receptors can modulate target gene expression. REV-ERB α, 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 α 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 α in the regulation of interleukin-6 (il6) gene expression in murine macrophages. REV-ERB α agonists, or overexpression of rev-erb α in the murine macrophage cell line RAW264 cells, suppressed the induction of il6 mRNA following a lipopolysaccharide (LPS) endotoxin challenge. Also, rev-erb α overexpression decreased LPS-stimulated nuclear factor B (NFB) activation in RAW264 cells. We showed that REV-ERB α represses il6 expression not only indirectly through an NFB binding motif but also directly through a REV-ERB α binding motif in the murine il6 promoter region. Furthermore, peritoneal macrophages from mice lacking rev-erb α increased il6 mRNA expression. These data suggest that REV-ERB α regulates the inflammatory response of macrophages through the suppression of il6 expression. REV-ERB α may therefore be identified as a potent anti-inflammatory receptor and be a therapeutic target receptor of inflammatory diseases.