Notch ligand Delta-1 differentially modulates the effects of gp130 activation on interleukin-6 receptor alpha-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-alpha subunit (IL-6Ralpha)(+) but also IL-6Ralpha(-) 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-6Ralpha, 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-6Ralpha(-) 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-6Ralpha(+) myeloid progenitors. These results indicate that Delta-1 interacts differentially with gp130 activation in IL-6Ralpha(-) erythroid and IL-6Ralpha(+) myeloid progenitors. The present data suggest a divergent interaction between Delta-1 and gp130 activation in human hematopoiesis.
Yamamura
Kentaro
K
Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Ohishi
Kohshi
K
Katayama
Naoyuki
N
Kato
Keizo
K
Shibasaki
Tetsunori
T
Sugimoto
Yuka
Y
Miyata
Eri
E
Shiku
Hiroshi
H
Masuya
Masahiro
M
Nishioka
Junji
J
Nobori
Tsutomu
T
Nishikawa
Mitsuo
M
Inagaki
Yoshimasa
Y
Hiramatsu
Hidefumi
H
Nakahata
Tatsutoshi
T
D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000494:pharmacology*; D003713:Dendritic Cells / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*
C494199:IL6ST protein, human; D007377:Interleukin-3; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D019947:Receptors, Interleukin-6; D051880:Receptors, Notch; C064045:delta protein; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130