The Role of C/EBPε in the Terminal Stages of Granulocyte Differentiation

Abstract

As a consequence of its characterization using both in vitro and knockout mouse models, the myeloid-specific transcription factor, CCAAT/enhancer binding protein (C/EBP)ε, has been identified as a critical regulator of terminal granulopoiesis and one of the causative mutations in the human disease, neutrophil-specific granule deficiency. C/EBPs are a family of transcription factors sharing numerous structural and functional features and to date include C/EBPα, -β, -γ, -δ, -ε, and -ζ. C/EBPα was the first family member isolated and characterized, its essential role in hepatocyte and adipocyte differentiation demonstrated in knockout mouse models. Subsequent analysis of the hematopoietic elements in fetal mouse liver revealed its critical role in myelopoiesis.Understanding

CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor

“…The phenotypes of mice lacking one or more C/EBP isoforms provide additional insight into the roles that endogenous C/EBPs play in granulopoiesis. Most strikingly, neutrophils from C/EBP⑀ Ϫ/Ϫ mice do not contain secondary granules, 22 and C/EBP␣ Ϫ/Ϫ neonates lack G-CSF-responsive progenitors and mature granulocytic cells. 15 In contrast, G-CSF Ϫ/Ϫ mice, G-CSFR Ϫ/Ϫ mice, and G-CSFR Ϫ/Ϫ /IL-6 receptor Ϫ/Ϫ mice retain significant numbers of marrow neutrophils, [47][48][49] indicating that C/EBP␣ contributes more to granulopoiesis than the activation of the genes encoding one or both of these cytokine receptors.…”

“…[18][19][20] C/EBP⑀ Ϫ/Ϫ mice also retain neutrophils, although they lack secondary granules. 21,22 The presence of several C/EBPs in the myeloid lineages suggests that related family members might compensate in vivo for the lack of a single isoform, just as GATA family members partially compensate for the lack of GATA-1. 23 Potential redundancy is evident from the ability of C/EBP␤ to compensate for the loss of C/EBP␣ in hepatocytes 24 and granulocytes (Y.-H. Lee, written personal communication, June 2001), from the ability of both C/EBP␣ and C/EBP⑀ to direct the granulocytic differentiation of myeloblastic cell lines, 11,25,26 from findings presented here indicating that C/EBP␤ or C/EBP␦ can direct 32D cl3 cell maturation, and from the expression of high-levels of G-CSFR messenger RNA (mRNA) in EML cell lines lacking C/EBP␣.…”

AML-1, PU.1, and Sp3 regulate expression of human bactericidal/permeability-increasing protein

“…C/EBP-family members often participate in the transcriptional regulation of genes coding for azurophil and specific granule proteins (reviewed in [55,56]). Two potential C/EBP-sites were found in the proximal BPIpromoter (Fig.…”

Stimulus-Dependent Impairment of the Neutrophil Oxidative Burst Response in Lactoferrin-Deficient Mice

“…21,22 C/EBP is a basic leucine zipper transcription factor expressed predominantly in myeloid cells that control the developmental expression of several genes associated with late-stage neutrophil differentiation. 23 The phenotype of C/EBP knockout mice closely resembles many aspects of the neutrophil defects observed in human SGD, including abnormal bilobed neutrophil morphology, impaired migration to the site of inflammatory challenge, reduced phagocytosis and bactericidal activity, and an impaired oxidative burst activity. 14,24,25 These mice succumb to opportunistic infections, usually caused by P. aeruginosa between 3 to 5 months.…”