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

Donald M. Lamkin, Shreyesi Srivastava, Karen P. Bradshaw, Jenna E. Betz, Kevin B. Muy, Anna M. Wiese, Shelby K. Yee, Rebecca M. Waggoner, Jesusa M.G. Arevalo, Alexander J. Yoon, Kym F. Faull, Erica K. Sloan, Steve W. Cole

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Number of pages10
JournalBrain, Behavior, and Immunity
DOIs
Publication statusAccepted/In press - 24 May 2019

Keywords

  • Adrenergic receptor
  • Bioinformatics
  • Functional genomics
  • Macrophage
  • Transcription factor
  • Tumor immunology

Cite this

Lamkin, D. M., Srivastava, S., Bradshaw, K. P., Betz, J. E., Muy, K. B., Wiese, A. M., ... Cole, S. W. (Accepted/In press). C/EBPβ regulates the M2 transcriptome in β-adrenergic-stimulated macrophages. Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2019.05.034
Lamkin, Donald M. ; Srivastava, Shreyesi ; Bradshaw, Karen P. ; Betz, Jenna E. ; Muy, Kevin B. ; Wiese, Anna M. ; Yee, Shelby K. ; Waggoner, Rebecca M. ; Arevalo, Jesusa M.G. ; Yoon, Alexander J. ; Faull, Kym F. ; Sloan, Erica K. ; Cole, Steve W. / C/EBPβ regulates the M2 transcriptome in β-adrenergic-stimulated macrophages. In: Brain, Behavior, and Immunity. 2019.
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abstract = "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.",
keywords = "Adrenergic receptor, Bioinformatics, Functional genomics, Macrophage, Transcription factor, Tumor immunology",
author = "Lamkin, {Donald M.} and Shreyesi Srivastava and Bradshaw, {Karen P.} and Betz, {Jenna E.} and Muy, {Kevin B.} and Wiese, {Anna M.} and Yee, {Shelby K.} and Waggoner, {Rebecca M.} and Arevalo, {Jesusa M.G.} and Yoon, {Alexander J.} and Faull, {Kym F.} and Sloan, {Erica K.} and Cole, {Steve W.}",
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Lamkin, DM, Srivastava, S, Bradshaw, KP, Betz, JE, Muy, KB, Wiese, AM, Yee, SK, Waggoner, RM, Arevalo, JMG, Yoon, AJ, Faull, KF, Sloan, EK & Cole, SW 2019, 'C/EBPβ regulates the M2 transcriptome in β-adrenergic-stimulated macrophages' Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2019.05.034

C/EBPβ regulates the M2 transcriptome in β-adrenergic-stimulated macrophages. / Lamkin, Donald M.; Srivastava, Shreyesi; Bradshaw, Karen P.; Betz, Jenna E.; Muy, Kevin B.; Wiese, Anna M.; Yee, Shelby K.; Waggoner, Rebecca M.; Arevalo, Jesusa M.G.; Yoon, Alexander J.; Faull, Kym F.; Sloan, Erica K.; Cole, Steve W.

In: Brain, Behavior, and Immunity, 24.05.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - C/EBPβ regulates the M2 transcriptome in β-adrenergic-stimulated macrophages

AU - Lamkin, Donald M.

AU - Srivastava, Shreyesi

AU - Bradshaw, Karen P.

AU - Betz, Jenna E.

AU - Muy, Kevin B.

AU - Wiese, Anna M.

AU - Yee, Shelby K.

AU - Waggoner, Rebecca M.

AU - Arevalo, Jesusa M.G.

AU - Yoon, Alexander J.

AU - Faull, Kym F.

AU - Sloan, Erica K.

AU - Cole, Steve W.

PY - 2019/5/24

Y1 - 2019/5/24

N2 - 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.

AB - 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.

KW - Adrenergic receptor

KW - Bioinformatics

KW - Functional genomics

KW - Macrophage

KW - Transcription factor

KW - Tumor immunology

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DO - 10.1016/j.bbi.2019.05.034

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