C/EBP? regulates the M2 transcriptome in ?-adrenergic-stimulated macrophages.

ABSTRACT: At the M2 terminal of the macrophage activation spectrum, expression of genes is regulated by transcription factors that include STAT6, CREB, and C/EBP?. Signaling through ?-adrenergic receptors drives M2 activation of macrophages, but little is known about the transcription factors involved. In the present study, we found that C/EBP? regulates the signaling pathway between ?-adrenergic stimulation and expression of Arg1 and several other specific genes in the greater M2 transcriptome. ?-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/EBP? 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 ?-adrenergic-induced peak in Cebpb gene expression as well as subsequent accumulation of C/EBP? protein in the nucleus, which resulted in suppression of ?-adrenergic-induced Arg1 gene expression. Analysis of genome-wide transcriptional profiles identified 20 additional M2 genes that followed the same pattern of regulation by ?-adrenergic- and C/EBP?-signaling. Promoter-based bioinformatic analysis confirmed enrichment of binding motifs for C/EBP? transcription factor across these M2 genes. These findings pinpoint a mechanism that may be targeted to redirect the deleterious influence of ?-adrenergic signaling on macrophage involvement in M2-related diseases such as cancer.

SUBMITTER: Lamkin DM 

PROVIDER: S-EPMC6660400 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature