Delta-1 Promotes Soluble IL-6R-Mediated Action of IL-6 on Human Erythropoiesis While Counteracting the Effect of IL-6 on the Generation of Myeloid-Lineage Cells.

Notch ligand Delta-1 is shown to influence proliferation and differentiation of hematopoietic progenitors by interacting with various cytokines. IL-6 exerts various effects on human hematopoiesis by activating gp130 via soluble IL-6 receptor (R) as well as membrane-bound IL-6R. However, little is known about the interaction between Delta-1 and gp130 activation in human hematopoiesis. We previously reported that Delta-1 in combination with IL-6R/IL-6 fusion protein FP6, which directly and agonistically activates gp130, enhances the production of mixed and pure erythroid progenitors from cord blood CD34⁺CD38⁻ cells, while not significantly affecting the generation of myeloid progenitors (ASH 2004). Here, we examined the interaction between Delta-1 and gp130 activation in the generation of erythroid cells and myeloid-lineage cells from cord blood CD34⁺CD38⁻ cells in serum-free suspension cultures. In the presence of SCF, Flt3L, TPO, and IL-3 (4GF), Delta-1 acted synergistically with FP6 to promote the production of CD36⁺glycophorin A (GPA)^high erythroid cells from CD34⁺CD38⁻ cells, whereas few CD36⁺GPA^high erythroid cells were generated by Delta-1, IL-6, and Delta-1 plus IL-6. When we assessed the stage of erythroid cells affected by Delta-1 and FP6, Delta-1, in conjunction with FP6, augmented the generation of CD36⁺GPA^high erythroid cells from CD34⁺CD38⁻ cell-derived CD36⁺GPA⁻ erythroid progenitors equivalent to BFU-E stage but not from CD34⁺CD38⁻cell-derived CD36⁺GPA^low erythroid progenitors equivalent to CFU-E stage. On the other hand, IL-6 and FP6 increased the production of CD14⁺ monocytic cells and CD15⁺ granulocytic cells from CD34⁺CD38⁻ cells. Delta-1 had opposite effect and antagonized the stimulatory effect of IL-6 and FP6 on the generation of monocytic and granulocytic cells. Although the development of CD1a⁺CD14⁻ dendritic cells from CD34⁺CD38⁻ cells was suppressed by IL-6 and FP6 but instead potentiated by Delta-1, Delta-1 competed with the inhibitory effect of IL-6 and FP6 on the generation of dendritic cells. These data indicate that Delta-1 modulates the effect of IL-6 on human hematopoiesis by enhancing its soluble IL-6R-mediated action on early erythropoiesis while antagonizing its effect on the generation of myeloid-lineage cells.