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Response of Monocyte Iron Regulatory Protein Activity to
Inflammation: Abnormal Behavior in Genetic Hemochromatosis
Stefania Recalcati,
Roberta Pometta,
Sonia Levi,
Dario Conte, and
Gaetano Cairo
From the Cattedra di Gastroenterologia I, Università degli
Studi, IRCCS Ospedale Maggiore; DIBIT Istituto Scientifico Ospedale San
Raffaele; and Centro di Studio sulla Patologia Cellulare CNR, Milano,
Italy.
In genetic hemochromatosis (GH), iron overload affects mainly
parenchymal cells, whereas little iron is found in reticuloendothelial (RE) cells. We previously found that RE cells from GH patients had an
inappropriately high activity of iron regulatory protein (IRP), the key
regulator of intracellular iron homeostasis. Elevated IRP should
reflect a reduction of the iron pool, possibly because of a failure to
retain iron. A defect in iron handling by RE cells that results in a
lack of feedback regulation of intestinal absorption might be the basic
abnormality in GH. To further investigate the capacity of iron
retention in RE cells of GH patients, we used inflammation as a model
system as it is characterized by a block of iron release from
macrophages. We analyzed the iron status of RE cells by assaying IRP
activity and ferritin content after 4, 8, and 24 hours of incubation
with lipopolysaccharide (LPS) and interferon- (IFN-).
RNA-bandshift assays showed that in monocytes and macrophages from 16 control subjects, IRP activity was transiently elevated 4 hours after
treatment with LPS and IFN- but remarkably downregulated thereafter.
Treatment with NO donors produced the same effects whereas an inducible
Nitric Oxide Synthase (iNOS) inhibitor prevented them, which suggests that the NO pathway was involved. Decreased IRP activity was also found
in monocytes from eight patients with inflammation. Interestingly, no
late decrease of IRP activity was detected in cytokine-treated RE cells
from 12 GH patients. Ferritin content was increased 24 hours after
treatment in monocytes from normal subjects but not in monocytes from
GH patients. The lack of downregulation of IRP activity under
inflammatory conditions seems to confirm that the control of iron
release from RE cells is defective in GH.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2565-2572
© 1998 by The American Society of Hematology.
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