REGULATION OF CELLULAR IRON-METABOLISM BY ERYTHROPOIETIN - ACTIVATIONOF IRON-REGULATORY PROTEIN AND UP-REGULATION OF TRANSFERRIN RECEPTOR EXPRESSION IN ERYTHROID-CELLS

Erythropoietin (Epo) is the central regulator of red blood cell produc tion 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, w e have investigated whether Epo can regulate cellular iron metabolism. We present here a novel biologic function of Epo, namely as a potenti al modulator of cellular iron homeostasis. We show that, in human (K56 2) and murine erythroleukemic cells (MEL), Epo enhances the binding af finity of iron-regulatory protein (IRP)-1, the central regulator of ce llular iron metabolism, to specific RNA stem-loop structures, known as iron-responsive elements (IREs). Activation of IRP-1 by Epo is associ ated with a marked increase in transferrin receptor (trf-rec) mRNA lev els 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 I RPs 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 no t 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 metabo lism by which Epo increases iron uptake into erythroid progenitor cell s via posttranscriptional induction of trf-rec expression. Our data su ggest that sequential administration of Epo and iron might improve the response to Epo therapy in some anemias. (C) 1997 by The American Soc iety of Hematology.