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.

Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. The latter involves regulation of the iron transporter ferroportin 1 by hepcidin. The mechanism of reduced plasma zinc is not known. Transcripts of the two zinc transporter gene families (ZnT and Zip) were screened for regulation in mouse liver after turpentine-induced inflammation and LPS administration. Zip14 mRNA was the transporter transcript most up-regulated by inflammation and LPS. IL-6 knockout (IL-6 ؊/؊ ) mice did not exhibit either hypozincemia or the induction of Zip14 with turpentine inflammation. However, in IL-6 ؊/؊ mice, LPS produced a milder hypozincemic response but no Zip14 induction. Northern analysis showed Zip14 up-regulation was specific for the liver, with one major transcript. Immunohistochemistry, using an antibody to an extracellular Zip14 epitope, showed both LPS and turpentine increased abundance of Zip14 at the plasma membrane of hepatocytes. IL-6 produced increased expression of Zip14 in primary hepatocytes cultures and localization of the protein to the plasma membrane. Transfection of mZip14 cDNA into human embryonic kidney cells increased zinc uptake as measured by both a fluorescent probe for free Zn 2؉ and 65 Zn accumulation, as well as by metallothionein mRNA induction, all indicating that Zip14 functions as a zinc importer. Zip14 was localized in plasma membrane of the transfected cells. These in vivo and in vitro experiments demonstrate that Zip14 expression is up-regulated through IL-6, and that this zinc transporter most likely plays a major role in the mechanism responsible for hypozincemia that accompanies the acute-phase response to inflammation and infection.endotoxemia ͉ inflammation ͉ hepatic ͉ Slc39a14 ͉ knockout mice

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...

Background and objectives: Hepcidin is a key regulator of iron homeostasis, but its study in the setting of chronic kidney disease (CKD) has been hampered by the lack of validated serum assays.Design, setting, participants, & measurements: This study reports the first measurements of bioactive serum hepcidin using a novel competitive ELISA in 48 pediatric (PCKD2-4) and 32 adult (ACKD2-4) patients with stages 2 to 4 CKD along with 26 pediatric patients with stage 5 CKD (PCKD5D) on peritoneal dialysis.Results: When compared with their respective controls (pediatric median ‫؍‬ 25.3 ng/ml, adult ‫؍‬ 72.9 ng/ml), hepcidin was significantly increased in PCKD2-4 (127.3 ng/ml), ACKD2-4 (269.9 ng/ml), and PCKD5D (652.4 ng/ml). Multivariate regression analysis was used to assess the relationship between hepcidin and indicators of anemia, iron status, inflammation, and renal function. In PCKD2-4 (R 2 ‫؍‬ 0.57), only ferritin correlated with hepcidin. In ACKD2-4 (R 2 ‫؍‬ 0.78), ferritin and soluble transferrin receptor were associated with hepcidin, whereas GFR was inversely correlated. In PCKD5D (R 2 ‫؍‬ 0.52), percent iron saturation and ferritin were predictors of hepcidin. In a multivariate analysis that incorporated all three groups (R 2 ‫؍‬ 0.6), hepcidin was predicted by ferritin, C-reactive protein, and whether the patient had stage 5D versus stages 2 to 4 CKD.Conclusions: These findings suggest that increased hepcidin across the spectrum of CKD may contribute to abnormal iron regulation and erythropoiesis and may be a novel biomarker of iron status and erythropoietin resistance.