Direct and Indirect Suppression of Interleukin-6 Gene Expression in Murine Macrophages by Nuclear Orphan Receptor REV-ERBα

It is now evident that many nuclear hormone receptors can modulate target gene expression. REV-ERBα, 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-ERBαplays a key role in the mediation between clockwork and inflammation. The purpose of the current study was to investigate the role of REV-ERBαin the regulation ofinterleukin-6(il6) gene expression in murine macrophages. REV-ERBαagonists, or overexpression ofrev-erbαin the murine macrophage cell line RAW264 cells, suppressed the induction ofil6mRNA following a lipopolysaccharide (LPS) endotoxin challenge. Also,rev-erbαoverexpression decreased LPS-stimulated nuclear factorκB (NFκB) activation in RAW264 cells. We showed that REV-ERBαrepressesil6expression not only indirectly through an NFκB binding motif but also directly through a REV-ERBαbinding motif in the murineil6promoter region. Furthermore, peritoneal macrophages from mice lackingrev-erbαincreasedil6mRNA expression. These data suggest that REV-ERBαregulates the inflammatory response of macrophages through the suppression ofil6expression. REV-ERBαmay therefore be identified as a potent anti-inflammatory receptor and be a therapeutic target receptor of inflammatory diseases.