C/EBPβ regulates the M2 transcriptome in β-adrenergic-stimulated macrophages

At the M2 terminal of the macrophage activation spectrum, expression of genes is regulated by transcription factors that include STAT6, CREB, and C/EBPβ. Signaling through β-adrenergic receptors drives M2 activation of macrophages, but little is known about the transcription factors involved. In the present study, we found that C/EBPβ regulates the signaling pathway between β-adrenergic stimulation and expression of Arg1 and several other specific genes in the greater M2 transcriptome. β-adrenergic signaling induced Cebpb gene expression relatively early with a peak at 1 h post-stimulation, followed by peak Arg1 gene expression at 8 h. C/EBPβ transcription factor activity was elevated at the enhancer region for Arg 1 at both 4 and 8 h after stimulation but not near the more proximal promoter region. Knockdown of Cebpb suppressed the β-adrenergic-induced peak in Cebpb gene expression as well as subsequent accumulation of C/EBPβ protein in the nucleus, which resulted in suppression of β-adrenergic-induced Arg1 gene expression. Analysis of genome-wide transcriptional profiles identified 20 additional M2 genes that followed the same pattern of regulation by β-adrenergic- and C/EBPβ-signaling. Promoter-based bioinformatic analysis confirmed enrichment of binding motifs for C/EBPβ transcription factor across these M2 genes. These findings pinpoint a mechanism that may be targeted to redirect the deleterious influence of β-adrenergic signaling on macrophage involvement in M2-related diseases such as cancer.