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Inappropriately high iron regulatory protein activity in monocytes of
patients with genetic hemochromatosis
G Cairo, S Recalcati, G Montosi, E Castrusini, D Conte and A Pietrangelo
Centro di Studio sulla Patologia Cellulare CNR, Universita degli Studi,
Milano, Italy.
In genetic hemochromatosis (GH), excess iron is deposited in parenchymal
cells, whereas little iron is found in reticuloendothelial (RE) cells until
the later stages of the disease. As iron absorption is inversely related to
RE cells stores, a failure of RE to retain iron has been proposed as the
basic defect in GH. In RE cells of GH subjects, we examined the activity of
iron regulatory protein (IRP), a reliable indicator of the elusive
regulatory labile iron pool, which modulates cellular iron homeostasis
through control of ferritin (Ft) and transferrin receptor gene expression.
RNA-bandshift assays showed a significant increase in IRP activity in
monocytes from 16 patients with untreated GH compared with 28 control
subjects (1.5-fold) and five patients with secondary hemochromatosis (SH)
with similar iron burden (fourfold). In 17 phlebotomy-treated GH patients,
IRP activity did not differ from that of control subjects. In both GH and
SH monocyte- macrophages, Ft content increased by twofold and the L
subunit-rich isoferritin profile was unchanged as compared with controls.
IRP activity was still upregulated in vitro in monocyte-derived macrophages
of GH subjects but, following manipulations of iron levels, was modulated
normally. Therefore, the sustained activity of monocyte IRP found in vivo
in monocytes of GH patients is not due to an inherent defect of its
control, but is rather the expression of a critical abnormality of iron
metabolism, eg, a paradoxical contraction of the regulatory iron pool. By
preventing Ft mRNA translation, high IRP activity in monocytes may
represent a molecular mechanism contributing to the inadequate Ft
accumulation and insufficient RE iron storage in GH.
Volume 89,
Issue 7,
pp. 2546-2553,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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