Notch ligand Delta-1 differentially modulates the effects of gp130 activation on interleukin-6 receptor α-positive and -negative human hematopoietic progenitors

Interleukin (IL)-6 plays pleiotropic roles in human hematopoiesis and immune responses by acting on not only the IL-6 receptor-α subunit (IL-6Rα)+ but also IL-6Rα− hematopoietic progenitors via soluble IL-6R. The Notch ligand Delta-1 has been identified as an important modulator of the differentiation and proliferation of human hematopoietic progenitors. Here, it was investigated whether these actions of IL-6 are influenced by Delta-1. When CD34+CD38− hematopoietic progenitors were cultured with stem cell factor, flt3 ligand, thrombopoietin and IL-3, Delta-1, in combination with the IL-6R/IL-6 fusion protein FP6, increased the generation of glycophorin A+ erythroid cells but counteracted the effects of IL-6 and FP6 on the generation of CD14+ monocytic and CD15+ granulocytic cells. Although freshly isolated CD34+CD38− cells expressed no or only low levels of IL-6Rα, its expression was increased in myeloid progenitors after culture but remained negative in erythroid progenitors. It was found that Delta-1 acted in synergy with FP6 to enhance the generation of erythroid cells from the IL-6Rα− erythroid progenitors. In contrast, Delta-1 antagonized the effects of IL-6 and FP6 on the development of monocytic and granulocytic cells, as well as CD14−CD1a+ dendritic cells, from the IL-6Rα+ myeloid progenitors. These results indicate that Delta-1 interacts differentially with gp130 activation in IL-6Rα− erythroid and IL-6Rα+ myeloid progenitors. The present data suggest a divergent interaction between Delta-1 and gp130 activation in human hematopoiesis. (Cancer Sci 2007; 98: 1597–1603)