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Regulation of cellular iron metabolism by erythropoietin: activation of
iron-regulatory protein and upregulation of transferrin receptor expression
in erythroid cells
G Weiss, T Houston, S Kastner, K Johrer, K Grunewald and JH Brock
Department of Internal Medicine, University Hospital, Innsbruck, Austria.
Erythropoietin (Epo) is the central regulator of red blood cell production
and acts primarily by inducing proliferation and differentiation of
erythroid progenitor cells. Because a sufficient supply of iron is a
prerequisite for erythroid proliferation and hemoglobin synthesis, we have
investigated whether Epo can regulate cellular iron metabolism. We present
here a novel biologic function of Epo, namely as a potential modulator of
cellular iron homeostasis. We show that, in human (K562) and murine
erythroleukemic cells (MEL), Epo enhances the binding affinity of
iron-regulatory protein (IRP)-1, the central regulator of cellular iron
metabolism, to specific RNA stem- loop structures, known as iron-responsive
elements (IREs). Activation of IRP-1 by Epo is associated with a marked
increase in transferrin receptor (trf-rec) mRNA levels in K562 and MEL,
enhanced cell surface expression of trf-recs, and increased uptake of iron
into cells. These findings are in agreement with the well-established
mechanism whereby high-affinity binding of IRPs to IREs stabilizes trf-rec
mRNA by protecting it from degradation by a specific RNase. The effects of
Epo on IRE-binding of IRPs were not observed in human myelomonocytic cells
(THP-1), which indicates that this response to Epo is not a general
mechanism observed in all cells but is likely to be erythroid-specific. Our
results provide evidence for a direct functional connection between Epo
biology and iron metabolism by which Epo increases iron uptake into
erythroid progenitor cells via posttranscriptional induction of trf-rec
expression. Our data suggest that sequential administration of Epo and iron
might improve the response to Epo therapy in some anemias.
Volume 89,
Issue 2,
pp. 680-687,
01/15/1997
Copyright © 1997 by The American Society of Hematology
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