TY - JOUR
T1 - Mutual inhibition of murine erythropoiesis and granulopoiesis during combined erythropoietin, granulocyte colony-stimulating factor, and stem cell factor administration: In vivo interactions and dose-response surfaces
AU - de Haan, G.
AU - Engel, C.
AU - Dontje, B.
AU - Nijhof, W.
AU - Loeffler, M.
PY - 1994
Y1 - 1994
N2 - We investigated the in vivo effects of erythropoietin (EPO) on granulopoiesis and, conversely, the effect of granulocyte colony-stimulating factor (G-CSF) treatment on erythropoiesis. Recombinant human EPO at four different doses in combination with recombinant human G-CSF also at four different doses was simultaneously administered for 7 days to splenectomized mice. In total, 16 different combinations of growth factors were thus tested. G-CSF administration increased granulocyte production as expected, whereas immature colony-forming unit granulocyte-macrophage numbers were decreased. EPO analogously increased late erythroid cell numbers. Both EPO and G-CSF dose-dependently inhibited late cell stages of the opposite lineage, with EPO abrogating G-CSF-stimulated granulopoiesis and, conversely, G-CSF inhibiting EPO-stimulated erythropoiesis. In a subsequent experiment, we tested whether these lineage-competitive effects could be prevented by coadministering stem cell factor (SCF). In these three factor-treated mice, all granuloid and erythroid cell stages increased, thereby reducing the effect of the mutual inhibition. We conclude that EPO-stimulated erythropoiesis and G-CSF- stimulated granulopoiesis inhibited each other at a late level. Simultaneous SCF administration increased the input into both the erythroid and granuloid compartment and thereby compensated the mutual inhibition. This study shows that intricate dose-response relationships exist between various growth factors that should be carefully analyzed before combinations of these factors are used in humans.
AB - We investigated the in vivo effects of erythropoietin (EPO) on granulopoiesis and, conversely, the effect of granulocyte colony-stimulating factor (G-CSF) treatment on erythropoiesis. Recombinant human EPO at four different doses in combination with recombinant human G-CSF also at four different doses was simultaneously administered for 7 days to splenectomized mice. In total, 16 different combinations of growth factors were thus tested. G-CSF administration increased granulocyte production as expected, whereas immature colony-forming unit granulocyte-macrophage numbers were decreased. EPO analogously increased late erythroid cell numbers. Both EPO and G-CSF dose-dependently inhibited late cell stages of the opposite lineage, with EPO abrogating G-CSF-stimulated granulopoiesis and, conversely, G-CSF inhibiting EPO-stimulated erythropoiesis. In a subsequent experiment, we tested whether these lineage-competitive effects could be prevented by coadministering stem cell factor (SCF). In these three factor-treated mice, all granuloid and erythroid cell stages increased, thereby reducing the effect of the mutual inhibition. We conclude that EPO-stimulated erythropoiesis and G-CSF- stimulated granulopoiesis inhibited each other at a late level. Simultaneous SCF administration increased the input into both the erythroid and granuloid compartment and thereby compensated the mutual inhibition. This study shows that intricate dose-response relationships exist between various growth factors that should be carefully analyzed before combinations of these factors are used in humans.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0027941695&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/7527670
U2 - https://doi.org/10.1182/blood.v84.12.4157.bloodjournal84124157
DO - https://doi.org/10.1182/blood.v84.12.4157.bloodjournal84124157
M3 - Article
C2 - 7527670
SN - 0006-4971
VL - 84
SP - 4157
EP - 4163
JO - Blood
JF - Blood
IS - 12
ER -