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