Cytokine-mediated regulation of iron transport in human monocytic cells

Under chronic inflammatory conditions cytokines induce a diversion of iron traffic, leading to hypoferremia and retention of the metal within the reticuloendothelial system. However, the regulatory pathways underlying these disturbances of iron homeostasis are poorly understood. We investigated tran...

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Bibliographic Details
Published in:Blood 2003-05, Vol.101 (10), p.4148-4154
Main Authors: Ludwiczek, Susanne, Aigner, Elmar, Theurl, Igor, Weiss, Günter
Format: Article
Language:English
Subjects:
Base Sequence
Biological and medical sciences
Biological Transport - drug effects
Cation Transport Proteins - blood
Cation Transport Proteins - genetics
Cytokines - pharmacology
DNA Primers
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Humans
Immunobiology
Interferon-gamma - pharmacology
Interleukin-10 - pharmacology
Iron - blood
Iron-Binding Proteins - blood
Iron-Binding Proteins - genetics
Kinetics
Lipopolysaccharides - pharmacology
Monocytes - drug effects
Monocytes - metabolism
Monocytes, macrophages
Myeloid cells: ontogeny, maturation, markers, receptors
Polymerase Chain Reaction
Receptors, Transferrin - blood
Receptors, Transferrin - drug effects
Tumor Cells, Cultured
U937 Cells
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Summary:Under chronic inflammatory conditions cytokines induce a diversion of iron traffic, leading to hypoferremia and retention of the metal within the reticuloendothelial system. However, the regulatory pathways underlying these disturbances of iron homeostasis are poorly understood. We investigated transferrin receptor (TfR)–dependent and –independent iron transport mechanisms in cytokine-stimulated human monocytic cell lines THP-1 and U937. Combined treatment of cells with interferon-γ (IFN-γ) and lipopolysaccharide (LPS) reduced TfR mRNA levels, surface expression, and iron uptake, and these effects were reversed by interleukin-10 (IL-10), thus stimulating TfR-mediated iron acquisition. IFN-γ and LPS dose-dependently increased the cellular expression of divalent metal transporter-1, a transmembrane transporter of ferrous iron, and stimulated the uptake of nontransferrin bound iron (NTBI) into cells. At the same time, IFN-γ and LPS down-regulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes. Preincubation with IL-10 partly counteracted these effects. Our results demonstrate that the proinflammatory stimuli IFN-γ and LPS increase the uptake of NTBI via stimulation of divalent metal transporter-1 expression and cause retention of the metal within monocytes by down-regulating ferroportin synthesis. Opposite, the anti-inflammatory cytokine IL-10 stimulates TfR-mediated iron uptake into activated monocytes. The regulation of iron transport by cytokines is a key mechanism in the pathogenesis of anemia of chronic disease and a promising target for therapeutic intervention.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2002-08-2459