Mechanisms of differential transferrin receptor expression in normal hematopoiesis

We have investigated the expression of transferrin receptor (TfR) iron regu latory protein-1 (IRP-1) and iron regulatory protein-2 (IRP-2) in liquid su spension culture of purified hematopoietic progenitor cells (HPCs) induced by a growth factor stimulus to proliferation and unilineage differentiation /maturation through the erythroid, granulocytic, monocytic and megakaryocyt ic lineages. In initial HPC differentiation, TfR expression is induced in both erythroid and granulopoietic cultures. In late HPC differentiation (i.e. starting fr om day 5 of culture) and then differentiated precursor maturation, the TfR gene is highly expressed in the erythroid lineage, whereas it is sharply do wnmodulated in the granulopoietic, monocytopoietic and megakaryocytic serie s. The elevated TfR expression in erythroid cells is: (a) mediated through a high rate of TfR gene transcription; (b) modulated by intracellular iron levels; (c) mediated by TfR mRNA stabilization through the iron regulatory protein (IRP), in that IRP-1 activity is high in erythroid lineage as compa red to the levels observed in other hemopoietic lineages; and (d) dependent on exogenous erythropoietin (Epo) (this is indicated by the marked TfR and IRP-1/IRP-2 downmodulation after Epo starvation). Interestingly, analysis of IRP-1 and IRP-2 expression during hemopoietic di fferentiation showed that: (a) IRP-1 expression was maintained during all s teps of erythroid differentiation, while it was lost in the other hemopoiet ic lineages; (b) IRP-2 expression was observed during all stages of hemopoi etic differentiation in all four lineages. However, IRP-1 and IRP-2 express ion and activity are induced when monocytes, which express only low levels of IRP-1 and IRP-2, are induced to maturation to macrophages. These studies indicate that: (a) in normal erythropoiesis, the hyperexpress ion of TfR, starting from early erythroid HPC differentiation, is Epo-depen dent and mediated via transcriptional and post-transcriptional mechanisms; (b) in the granulopoietic, monocytopoietic and megakaryocytic pathways, the TfR is first induced and then downmodulated (the latter phenomenon is medi ated via transcriptional suppression of the TfR gene and IRP inactivation).