TY - JOUR T1 - Interferon-gamma limits the availability of iron for intramacrophage Salmonella typhimurium. JF - Eur J Immunol Y1 - 2008 A1 - Nairz, Manfred A1 - Fritsche, Gernot A1 - Peter Brunner A1 - Talasz, Heribert A1 - Hantke, Klaus A1 - Weiss, Günter KW - Acute-Phase Proteins KW - Animals KW - Antimicrobial Cationic Peptides KW - Cation Transport Proteins KW - Cell Line KW - Ferritins KW - Heme Oxygenase (Decyclizing) KW - Hepcidins KW - Interferon-gamma KW - Iron KW - Lipocalins KW - Macrophages KW - Mice KW - Nitric Oxide KW - Oncogene Proteins KW - Salmonella typhimurium KW - Transferrin KW - Tumor Necrosis Factor-alpha AB -

In stimulating effector functions of mononuclear phagocytes, IFN-gamma is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN-gamma is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN-gamma on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella-infected phagocytes, IFN-gamma caused a significant reduction of iron uptake via transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore-capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN-gamma exerting a super-inducing effect. This observed regulatory impact of IFN-gamma reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF-alpha production. Our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN-gamma concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity.

VL - 38 UR - http://www.ncbi.nlm.nih.gov/pubmed/18581323 IS - 7 ER - TY - JOUR T1 - Pathways for the regulation of body iron homeostasis in response to experimental iron overload. JF - J Hepatol Y1 - 2005 A1 - Theurl, Igor A1 - Ludwiczek, Susanne A1 - Eller, Philipp A1 - Seifert, Markus A1 - Artner, Erika A1 - Peter Brunner A1 - Weiss, Günter KW - Animals KW - Disease Models, Animal KW - Disease Progression KW - DNA Primers KW - Duodenum KW - Gene Expression Regulation KW - Hepatocytes KW - Homeostasis KW - Iron KW - Iron Overload KW - Macrophages KW - Mice KW - Mice, Inbred C57BL KW - Polymerase Chain Reaction KW - RNA AB - BACKGROUND/AIMS: Secondary iron overload is a frequent clinical condition found in association with multiple blood transfusions. METHODS: To gain insight into adaptive changes in the expression of iron genes in duodenum, liver and spleen upon experimental iron overload we studied C57BL/6 mice receiving repetitive daily injections of iron-dextran for up to 5 days. RESULTS: Iron initially accumulated in spleen macrophages but with subsequent increase in macrophage ferroportin and ferritin expression its content in the spleen decreased while a progressive storage of iron occurred within hepatocytes which was paralleled by a significant increase in hepcidin and hemojuvelin expression. Under these conditions, iron was still absorbed from the duodenal lumen as divalent metal transporter-1 expressions were high, however, most of the absorbed iron was incorporated into duodenal ferritin, while ferroportin expression drastically decreased and iron transfer to the circulation was reduced. CONCLUSIONS: Experimental iron overload results in iron accumulation in macrophages and later in hepatocytes. In parallel, the transfer of iron from the gut to the circulation is diminished which may be referred to interference of hepcidin with ferroportin mediated iron export, thus preventing body iron accumulation. VL - 43 UR - http://www.sciencedirect.com/science/article/pii/S0168827805003168# IS - 4 ER -