title: IL-5 triggers a cooperative cytokine network that promotes eosinophil precursor maturation.
abstract: Eosinophils originate in the bone marrow from an eosinophil lineage-committed, IL-5Rα-positive, hematopoietic progenitor (eosinophil progenitor). Indeed, IL-5 is recognized as a critical regulator of eosinophilia and has effects on eosinophil progenitors, eosinophil precursors, and mature eosinophils. However, substantial levels of eosinophils remain after IL-5 neutralization or genetic deletion, suggesting that there are alternative pathways for promoting eosinophilia. In this study, we investigated the contributory role of IL-5 accessory cytokines on the final stages of eosinophil differentiation. IL-5 stimulation of low-density bone marrow cells resulted in expression of a panel of cytokines and cytokine receptors, including several ligand-receptor pairs. Notably, IL-4 and IL-4Rα were expressed by eosinophil precursors and mature eosinophils. Signaling through IL-4Rα promoted eosinophil maturation when IL-5 was present, but IL-4 stimulation in the absence of IL-5 resulted in impaired eosinophil survival, suggesting that IL-4 cooperates with IL-5 to promote eosinophil differentiation. In contrast, CCL3, an eosinophil precursor-produced chemokine that signals through CCR1, promotes terminal differentiation of CCR1-positive eosinophil precursors in the absence of IL-5, highlighting an autocrine loop capable of sustaining eosinophil differentiation. These findings suggest that brief exposure to IL-5 is sufficient to initiate a cytokine cooperative network that promotes eosinophil differentiation of low-density bone marrow cells independent of further IL-5 stimulation.
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Fulkerson
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Kaila L
authors.initials: KL
authors.lastname: Schollaert
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
authors.forename: Carine
authors.initials: C
authors.lastname: Bouffi
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229 Rothenberg@cchmc.org.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000096:biosynthesis / Q000276:immunology; D004802:Eosinophilia / Q000276:immunology; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology; D005260:Female; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D015848:Interleukin-5 / Q000494:pharmacology*; D053666:Interleukin-5 Receptor alpha Subunit / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D054389:Receptors, CCR1 / Q000096:biosynthesis / Q000276:immunology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D054405:Chemokine CCL3; D015847:Interleukin-4; D015848:Interleukin-5; D053666:Interleukin-5 Receptor alpha Subunit; D054389:Receptors, CCR1; D011956:Receptors, Cell Surface; C496534:Ccl3 protein, mouse; C515301:Ccr1 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit