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.

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