Response of monocyte iron regulatory protein activity to inflammation: abnormal behavior in genetic hemochromatosis.
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-gamma (IFN-gamma). 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-gamma 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.
Recalcati
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S
Cattedra di Gastroenterologia I, Università degli Studi, IRCCS Ospedale Maggiore, Milano, Italy.
Pometta
R
R
Levi
S
S
Conte
D
D
Cairo
G
G
D000328:Adult; D005260:Female; D006432:Hemochromatosis / Q000097:blood* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D012157:Mononuclear Phagocyte System / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D016601:RNA-Binding Proteins; D007501:Iron