Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.

Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.

Hepcidin, the principal iron regulatory hormone, regulates the absorption of iron from the diet and the mobilization of iron from stores. Previous studies indicated that hepcidin is suppressed during anemia, a response that would appropriately increase the absorption of iron and its release from stores. Indeed, in the mouse model, hepcidin-1 was suppressed after phlebotomy or erythropoietin administration but the suppression was reversed by inhibitors of erythropoiesis. The suppression of hepcidin necessary to match iron supply to erythropoietic demand thus re- IntroductionIt has long been thought that intestinal iron absorption and the mobilization of iron from stores is controlled by the combined action of 2 regulators: the stores regulator and the erythroid regulator. 1 The stores regulator controls intestinal iron absorption and is responsible for meeting the body's normal iron requirement and for accumulating and controlling iron stores. The erythroid regulator maintains the production of erythrocytes irrespective of the body's iron balance. In persistent anemia due to blood loss, this process increases iron absorption and depletes iron stores. In anemias with ineffective erythropoiesis, the erythroid regulator also increases iron absorption but, in the absence of iron losses, the accumulation of iron eventually results in iron overload. It has been demonstrated that the erythroid regulator can facilitate the absorption of iron up to 40 mg/d in severe anemia with oral iron supplementation compared with the stores regulator, which seems to only permit absorption of up to 2 mg iron/d. 1 More recently, the molecular basis of systemic iron regulation began to be understood. Hepcidin, the principal iron regulatory hormone, blocks the intestinal absorption of iron and the release of iron from stores by inducing the internalization and degradation of the cellular iron exporter ferroportin. 2 Ferroportin is the sole known cellular iron exporter and is found on the basolateral surface of duodenal enterocytes as well as on macrophages and hepatocytes. 3 Hepcidin is regulated both by iron and anemia and has been proposed as the final mediator of both the stores and erythroid regulators.The amount of iron in red blood cells is so large that increases in erythropoiesis require a considerable increase in the flow of iron from the diet or storage pools. For example, in patients with postoperative anemia, hemoglobin (Hgb) reportedly increases from 106 to 130 g/L (10.6-13.0 g/dL) during postoperative days 7 to 21. 4 Given an average blood volume of 5 L, this increment obligates 420 mg iron, or 30 mg/d. Given that baseline iron absorption is only 1 mg/d, iron absorption and release from stores must increase dramatically to compensate for this massive increase in iron consumption by erythropoietic precursors. Similarly, iron consumption for erythropoiesis increases greatly after stimulation with erythropoietin (EPO) or in response to hypoxemia. EPO treatment at doses of 100 U/kg 3 times a week leads to an average increase in...

Inherited anemias with ineffective erythropoiesis, such as β-thalassemia, manifest inappropriately low hepcidin production and consequent excessive absorption of dietary iron, leading to iron overload. Erythroferrone (ERFE) is an erythroid regulator of hepcidin synthesis and iron homeostasis. Erfe expression was highly increased in the marrow and spleen of HbbTh3/+ mice (Th3/+), a mouse model of thalassemia intermedia. Ablation of Erfe in Th3/+ mice restored normal levels of circulating hepcidin at 6 weeks of age, suggesting ERFE could be a factor suppressing hepcidin production in β-thalassemia. We examined the expression of Erfe and the consequences of its ablation in thalassemic mice from 3 to 12 weeks of age. The loss of ERFE in thalassemic mice led to full restoration of hepcidin mRNA expression at 3 and 6 weeks of age, and significant reduction in liver and spleen iron content at 6 and 12 weeks of age. Ablation of Erfe slightly ameliorated ineffective erythropoiesis, as indicated by reduced spleen index, red cell distribution width, and mean corpuscular volume, but did not improve the anemia. Thus, ERFE mediates hepcidin suppression and contributes to iron overload in a mouse model of β-thalassemia.

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-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-