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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-08-2459. This Article Full Text (PDF) All Versions of this Article: 2002-08-2459v1 101/10/4148    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ludwiczek, S. Articles by Weiss, G. Search for Related Content PubMed PubMed Citation Articles by Ludwiczek, S. Articles by Weiss, G. Social Bookmarking                   What's this? Submitted August 9, 2002 Accepted January 7, 2003 Cytokine mediated regulation of iron transport in human monocytic cells Susanne Ludwiczek, Elmar Aigner, Igor Theurl, and Guenter Weiss* Department of Internal Medicine, University of Innsbruck, Innsbruck, Austria * Corresponding author; email: guenter.weiss{at}uibk.ac.at. 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 IFN- and LPS reduced TfR mRNA levels, surface expression and iron uptake, and these effects were reversed by IL-10 thus stimulating TfR mediated iron acquisition. IFN- and LPS dose-dependently increased the cellular expression of divalent metal transporter-1, a transmembrane transporter of ferrous iron, and stimulated the uptake of non-transferrin bound iron (NTBI) into cells. At the same time, IFN- and LPS down-regulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes. Pre-incubation with IL-10 partly counteracted these effects. Our results demonstrate that the pro-inflammatory stimuli, IFN- 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. 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