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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
G de Haan, C Engel, B Dontje, W Nijhof and M Loeffler
Groningen Institute for Drug Studies, Department of Hematology, University
of Groningen, The Netherlands.
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.
Volume 84,
Issue 12,
pp. 4157-4163,
12/15/1994
Copyright © 1994 by The American Society of Hematology
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