Mice overexpressing IL-5 under the promoter of CD2, see a profound eosinophilia in the blood and spleen but also in the bone marrow ( Dent et al., 1990 Lee et al., 1997b Mishra et al., 2002b Tominaga et al., 1991). But IL-5 is also responsible for selective differentiation of eosinophils and this has been clearly demonstrated in genetically modified animals ( Sanderson, 1992). In 1995, using a high systemic level of IL-5, after intravenous injection, Collins et al have shown that mice developed blood eosinophilia and a depletion of bone marrow eosinophils, suggesting that IL-5 stimulates the release of eosinophils from the bone marrow into the peripheral circulation ( Collins et al., 1995). Indeed, of these three cytokines, IL-5 is the most specific to the eosinophil lineage. IL-3 and GM-CSF also induce the differentiation of other myeloid cells such as the mast cell, but IL-3, GM-CSF and IL-5 synergize toward the differentiation of eosinophils. In addition to a close proximity on the chromosome and a relative homology of sequence, IL-3, IL-5 and GM-CSF also share the common beta chain in their receptor in addition to the specific alpha chains ( Vadas et al., 1994). Located on chromosome 5 in position q31, IL-3, IL-5, and GM-CSF are particularly important in regulating eosinophil development ( Lopez et al., 1986 Lopez et al., 1988 Rothenberg et al., 1988 Takatsu et al., 1994). While expressing GATA-1 in other myeloid cells mast cells, megakaryocytes, and erythroid cells of the double GATA-1 deficient mice, they do not appear to be affected by the mutation in the high affinity palindromic GATA site ( Du et al., 2002).Ĭytokines are indispensable for hematopoietic cell development differentiation and maturation. The critical role for GATA-1 in eosinophil lineage was also confirmed by in vitro experiments ( Hirasawa et al., 2002 Iwasaki et al., 2005). The targeted mutation of the double GATA binding site present in the GATA-1 gene leads to the loss of the eosinophil lineage in mice ( Yu et al., 2002). The GATA-1 binding site is present as a palindromic sequence (double GATA site) in numerous eosinophil related genes (granule protein genes, CC-chemokine receptor 3, IL-5 receptor) and in the GATA-1 gene itself ( Du et al., 2002 Yu et al., 2002 Zimmermann et al., 2000a). Located on the chromosome X in humans and mice, GATA-1 transcription factor was named by its ability to bind the promoter sequence composed of the bases GATA. Of these transcription factors, GATA-1 is clearly the most important for eosinophil lineage specification. In most cells, PU.1 antagonizes with GATA-1, but they have synergistic activity in regulating eosinophil lineage specification and eosinophil granule protein transcription ( Du et al., 2002). On the other side, high levels of PU.1 lead to an increase myeloid differentiation ( McNagny and Graf, 2002 Nerlov and Graf, 1998 Nerlov et al., 1998). PU.1 is necessary for dictating monocyte/macrophage and dendritic cell commitment and differentiation, and for neutrophil differentiation. PU.1 gene-disrupted mice are devoid of B and dendritic cells, monocytes/macrophages, and mature neutrophils. PU.1 expression level determines the faith of the cell. At an early time point of the differentiation, PU.1 is involved in the switching between lymphoid and myeloid lineage. PU.1, an ets transcription factor family member, is only expressed in hematopoietic cells. Indeed, a transient activation of a conditional C/EBP form in multipotent progenitors lead to the formation of immature eosinophils, whereas sustained activation produced mature eosinophils, suggesting that C/EBP functions are required during eosinophil lineage commitment and maturation. As such, C/EBP-induced eosinophil differentiation can be separated into two distinct events, lineage commitment and maturation. Conversely, dominant-negative versions of C/EBP inhibits myeloid differentiation ( Nerlov et al., 1998). Forced expression of the transcription C/EPB members (CCAAT/enhancer-binding protein family) in progenitor cells induces myeloid and eosinophil differentiation ( Nerlov et al., 1998). Several transcription factors are involved in the eosinophilic lineage.
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