Interleukin-5 Receptor α Subunit Gene Regulation in Human Eosinophil Development: Identification of a Unique Cis-Element that acts lie an Enhacer in Regulating Activity of the IL-5Rα Promoter

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Abstract
The molecular basis for the commitment of multipotential myeloid progenitors to the eosinophil lineage, and the transcriptional mechanisms by which eosinophil-specific genes are subsequently expressed and regulated during eosinophil development are currently unknown. IL-5, produced primarily by activated T cells [1] and mast cells [2], is integral to both the differentiation and functional maturation of the human eosinophil lineage [3-6]. The development and maturation of eosinophils in the bone marrow, and their post-mitotic functional activation in tissues occurs in response to a number of cytokines in addition to IL-5, including GM-CSF and IL-3 [7-9]. In humans, both IL-3 and GM-CSF have activities on other hematopoietic lineages, whereas IL-5 is eosinophil-specific and plays a crucial role in regulating the differentiation and development of the eosinophil lineage [3]. Although IL-3 and GM-CSF participate in the proliferation and committment of progenitors to the eosinophil lineage, IL-5 is both necessary and sufficient for eosinophil development to proceed[3, 10]. In humans, the high affinity receptor for IL-5 is apparently restricted to eosinophils and hematopoietically related basophils [11]; in contrast to murine B cells, the activity of IL-5 on human B cells is controversial [3, 12] and is still being delineated [13]. Thus, the expression of the high-affinity receptor for IL-5 is an important prerequisite and very early lineage-specific event in the hematopoietic program for these granuloctyes. Overexpression of IL-5 is observed in many eosinophil-associated diseases [14-16] and IL-5 transgenic mice develop profound eosinophilia [4, 5], indicating that IL-5 plays critical roles in promoting the production and function of eosinophils in vivo Of note, IL-5 is also active in vitro both in the production of eosinophils from bone marrow, umbilical cord and peripheral blood progenitors, as well as in the priming, activation and enhanced survival of mature eosinophils.