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.
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
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G de Haan, C Engel, B Dontje, W Nijhof, M Loeffler; 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. Blood 1994; 84 (12): 4157–4163. doi: https://doi.org/10.1182/blood.V84.12.4157.bloodjournal84124157
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