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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

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

Lamkin Donald M DM Srivastava Shreyesi S Bradshaw Karen P KP Betz Jenna E JE Muy Kevin B KB Wiese Anna M AM Yee Shelby K SK Waggoner Rebecca M RM Arevalo Jesusa M G JMG Yoon Alexander J AJ Faull Kym F KF Sloan Erica K EK Cole Steve W SW

Brain, behavior, and immunity 20190524

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-adrener ...[more]

PMID: 31132458

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Project description:BACKGROUND:An uncontrolled inflammatory response is a critical pathophysiological feature of sepsis. Mesenchymal stem cells (MSCs) induce macrophage phenotype polarization and reduce inflammation in sepsis. MSC-secreted transforming growth factor beta (TGF-β) participated in the immune modulatory function of MSCs. However, the underlying mechanism of MSC-secreted TGF-β was not fully elucidated in regulation macrophage M2-like polarization. METHODS:The paracrine effects of MSCs on macrophage polarization were studied using a co-culture protocol with LPS-stimulated RAW264.7 cells/mouse peritoneal macrophages and MSCs. The effect of TGF-β in the co-culture system was blocked by the TGF-β receptor inhibitor. To determine the role of MSC-secreted TGF-β, we used recombinant TGF-β to culture with LPS-stimulated RAW264.7 cells. In addition, we employed antibody microarray analysis to determine the mechanisms of MSC secreted TGF-β on LPS-stimulated RAW264.7 cell/mouse peritoneal macrophage M2-like polarization. Furthermore, we used an Akt inhibitor and a FoxO1 inhibitor to inhibit the Akt/FoxO1 pathway. The nuclear translocation of FoxO1 was detected by Western blot. RESULTS:MSCs induced LPS-stimulated RAW264.7 cell/mouse peritoneal macrophage polarization towards the M2-like phenotype and significantly reduced pro-inflammatory cytokine levels via paracrine, which was inhibited by TGF-β receptor inhibitor. Furthermore, we found that MSC-secreted TGF-β enhanced the macrophage phagocytic ability. The antibody microarray analysis and Western blot verified that TGF-β treatment activated the Akt/FoxO1 pathway in LPS-stimulated macrophages, TGF-β-induced FoxO1 nuclear translocation and obviously expressed in the cytoplasm, the effects of TGF-β regulatory effects on LPS-stimulated macrophage were inhibited by pre-treatment with Akt inhibitor and FoxO1 inhibitor. CONCLUSIONS:TGF-β secreted by MSCs could skew LPS-stimulated macrophage polarization towards the M2-like phenotype, reduce inflammatory reactions, and improve the phagocytic ability via the Akt/FoxO1 pathway, providing potential therapeutic strategies for sepsis.

Dataset Information

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

Publications

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

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