Hepcidin is the principal iron regulatory hormone and its overproduction contributes to anemia of inflammation (AI). In vitro, hepcidin binds to and induces the degradation of the exclusive iron exporter ferroportin. We explored the effects and distribution of synthetic hepcidin in the mouse. A single intraperitoneal injection of hepcidin caused a rapid fall of serum iron in a dose-dependent manner, with a 50-mu g dose resulting in iron levels 80% lower than in control mice. The full effect was seen within only 1 hour, consistent with a blockade of iron export from tissue stores and from macrophages involved in iron recycling. Serum iron remained suppressed for more than 48 hours after injection. Using radiolabeled hepcidin, we demonstrated that the serum concentration of hepcidin at the 50 mu g dose was 1.4 mu M, consistent with the inhibitory concentration Of 50% (IC50) Of hepcidin measured in vitro. Radiolabeled hepcidin accumulated in the ferroportin-rich organs, liver, spleen, and proximal duodenum. Our study highlights the central role of the hepcidin-ferroportin interaction in iron homeostasis. The rapid and sustained action of a single dose of hepcidin makes it an appealing agent for the prevention of iron accumulation in hereditary hemochromatosis.

The iron-regulatory hormone hepcidin has been proposed as the mediator of anemia of inflammation (AI). We examined the acute and chronic effects of hepcidin in the mouse. Injections of human hepcidin (50 mug/mouse), but not of its diluent, induced hypoferremia within 4 hours. To examine the chronic effects of hepcidin, we implanted either tumor xenografts engineered to overexpress human hepcidin or control tumor xenografts into nonobeseediabetic-severe combined immunodeficiency (NOD-SCID) mice. Despite abundant dietary iron, mice with hepcidin-producing tumors developed more severe anemia, lower serum iron, and increased hepatic iron compared with mice with control tumors. Hepcidin contributes to AI by shunting iron away from erythropoiesis and sequestering it in the liver, predominantly in hepatocytes. (C) 2005 by The American Society of Hematology.