期刊
JOURNAL OF IMMUNOLOGY
卷 193, 期 8, 页码 4043-4052出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1400732
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资金
- National Institutes of Health [R37 AI045898, R01 AI083450, K08 AI093673, P30 DK078392]
- Buckeye Foundation
- Food Allergy Research and Education
- Campaign Urging Research for Eosinophilic Disease
Eosinophils originate in the bone marrow from an eosinophil lineage-committed, IL-5R alpha-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-4R alpha were expressed by eosinophil precursors and mature eosinophils. Signaling through IL-4R alpha 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.
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