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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
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Myeloid transcription factor C/EBPepsilon is involved in the positive regulation of lactoferrin gene expression in

W Verbeek1, J Lekstrom-Himes, D J Park

  • 1Division of Hematology/Oncology, the Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA.

Blood
|November 11, 1999
PubMed

Insights

Mice lacking the myeloid transcription factor C/EBPepsilon (C/EBPepsilon-/-) die from gram-negative sepsis due to impaired granulocytic differentiation and reduced antimicrobial peptide production. This study reveals C/EBPepsilon

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Targeted mutation of the myeloid transcription factor C/EBPepsilon (C/EBPepsilon-/-) in mice leads to fatal gram-negative septic shock.
  • This phenotype is linked to defects in terminal granulocytic differentiation and compromised host defense mechanisms.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the granulocytic differentiation defects in C/EBPepsilon-/- mice.
  • To investigate the role of C/EBPepsilon in regulating genes crucial for antimicrobial defense, particularly lactoferrin.

Main Methods:

  • Analysis of bone marrow cells from C/EBPepsilon-/- mice for gene and protein expression of antimicrobial peptides and granule proteins.
  • Assessment of superoxide production and NADPH oxidase component levels (gp91 phox, p47phox) in myeloid cells.
  • Electromobility shift assays and reporter gene assays to determine C/EBPepsilon's direct binding to and regulation of the murine lactoferrin promoter.

Main Results:

  • C/EBPepsilon-/- mice exhibited near-complete absence of cathelin-related antimicrobial peptide precursor mRNA and reduced superoxide production.
  • Significantly reduced levels of p47phox protein and impaired NADPH oxidase assembly were observed in C/EBPepsilon-/- myeloid cells.
  • Expression of lactoferrin, gelatinase, and neutrophil collagenase mRNA was diminished or absent in C/EBPepsilon-/- mice; C/EBPepsilon directly binds and activates the lactoferrin promoter.

Conclusions:

  • C/EBPepsilon is essential for host antimicrobial defense, particularly against gram-negative bacteria.
  • C/EBPepsilon plays a direct role in regulating the expression of key antimicrobial proteins like lactoferrin, impacting granulocytic function and sepsis survival.

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