Overproduction Of Hepcidin Research Articles

TMPRSS6- Mutation in Iron Deficiency Anemia: A Review

Introduction: Iron is one of the metals involved in a variety of physiological reactions, including the construction of haemoglobin, which transports oxygen to the tissues. Chronic blood loss or insufficient food intake are the most common causes of iron insufficiency.. A germline mutation in TMPRSS6, which encodes type two transmembrane serine protease generated by the liver and helps regulate the expression of systemic iron, can induce anaemia that is resistant to oral iron treatment.
 Structure: The plasma membrane is cleaved by TMPRSS6 in vitro. The signalling mechanism required for iron-dependent hepcidin transcription regulation is thought to be downregulated by TMPRSS6. They also investigated whether the robust physiologic inducer of hepcidin, iron, can affect TMPRSS6 mRNA levels in vivo, as one of the most important activators of hepcidin expression in vitro and in vivo.
 Role of TMPRSS6: Overexpression of normal TMPRSS6 protein reduces Hamp promoter activity, and the TMPRSS6 cytoplasmic domain mediates Hamp suppression via the proximal promoter element. TMPRSS6 polymorphisms are more common than mutations and have been linked to variations in iron and hematologic markers.
 Conclusion: Because TMPRSS6 is linked to haematological factors, it is essential for maintaining iron homeostasis and proper erythropoiesis. Overproduction of hepcidin is caused by the TMPRSS6 mutation, which contributes to poor iron absorption and utilisation. Patients with poor transferrin saturation, normal ferritin levels, high amounts of hepcidin molecules, and a family history of iron deficiency anemia should be aware of TMPRSS6 gene mutations.

Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model.

Objectives: Probenecid is an anion transport inhibitor, which, according to the connectivity map (CMap; a biological application database), interferes with hypoxia-induced gene expression changes in retinal vascular endothelial cells (ECs). Here, we investigated the influence of probenecid on retinal EC cytotoxicity and retinal neovascularization in a murine oxygen-induced retinopathy (OIR) model. Methods: The retinal EC growth rate in the presence of hypoxia-mimicking concentrations of cobalt chloride (CoCl2) was determined using the thiazolyl blue tetrazolium bromide (MTT) assay and proliferating cell nuclear antigen (PCNA) expression. In OIR rats, probenecid was administered by intraperitoneal injection (i.p.) from postnatal day (P) 1 to P7. The concentrations of vitreous humor vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α, and placental growth factor (PlGF) were determined by using the ELISA kit at P21. The amount of newly formed vascular lumen was evaluated by histopathological examination. Retinopathy and neovascularization were assessed by scoring isolectin B4 fluorescein–stained retinal flat mounts. Western blots for liver tissue HIF-1α and hepcidin (HAMP) were performed. Results: In vitro, probenecid led to the recession of the hypoxia-induced EC growth rate. In vivo, compared to the OIR retina, the upregulation of VEGF, HIF-1α, and PlGF in phase II retinopathy of prematurity (ROP) was inhibited by probenecid administration. Moreover, probenecid ameliorated neovascularization and resulted in significantly reduced relative leakage fluorescence signal intensity in fluorescein-stained retinal flat mounts (p < 0.05). Probenecid alleviated the liver overactivation of HAMP and downregulation of HIF-1α in OIR rats. Conclusions: This is the first demonstration that implies that probenecid might be a protective compound against retinal angiogenesis in OIR. These changes are accompanied with decreased hyperoxia-mediated hepcidin overproduction. Although the relevance of the results to ROP needs further research, these findings may help establish potential pharmacological targets based on the CMap database.

Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis.

Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.

Collagen Hydrolysate Corrects Anemia in Chronic Kidney Disease via Anti-Inflammatory Renoprotection and HIF-2α-Dependent Erythropoietin and Hepcidin Regulation.

Anemia is a common chronic kidney disease (CKD) complication contributing to increased morbidity and mortality. Collagen-based traditional Chinese nutraceuticals have long been used in antianemic therapies. This study aims to investigate the therapeutic effectiveness of porcine collagen hydrolysate (CH) and its underlying mechanism in the treatment of renal anemia by using adenine-induced CKD mice, RAW264.7 macrophages, and HepG2 hepatoma cells, with prolyl-hydroxyproline as a reference compound for collagen-derived hydroxyproline-containing di-/tripeptides. CH was found to alleviate renal filtering dysfunction, systemic and kidney inflammation, liver hepcidin overproduction and anemia and to increase erythropoietin production and hypoxia inducible factor (HIF)-2α stability in liver and kidney in CKD mice. Prolyl-hydroxyproline exerted direct anti-inflammatory effects on lipopolysaccharide-activated macrophages and elicited stimulating and inhibiting activities on erythropoietin expression and hepcidin overproduction, respectively, in HepG2 cells by HIF-2α activation. Overall, CH was effective in correcting renal anemia via anti-inflammatory renoprotection and HIF-2α-dependent erythropoietin and hepcidin regulation.

3-Amidinophenylalanine-derived matriptase inhibitors can modulate hepcidin production in vitro

Matriptase-2 (MT-2) is a type II transmembrane serine protease and predominantly attached to the surface of hepatocytes. MT-2 decreases the production of hepcidin, a key regulator of iron homeostasis. In this study, the effects of four 3-amidinophenylalanine-derived combined matriptase-1/matriptase-2 (MT-1/2) inhibitors (MI-432, MI-441, MI-460, and MI-461) on hepcidin production were investigated in hepatocyte mono- and hepatocyte-Kupffer cell co-cultures. In MI-461-treated cell cultures, the extracellular hydrogen peroxide contents and the interleukin-6 and -8 (IL-6 and IL-8) levels were determined and compared to controls. Hepcidin overproduction was observed in hepatocytes upon treatment with MI-432, MI-441 and MI-461 at 50 μM. In contrast, extracellular hydrogen peroxide levels were not elevated significantly after matriptase inhibition with MI-461. Furthermore, MI-461 did not induce increases in IL-6 and IL-8 levels in these hepatic models. A model of the binding mode of inhibitor MI-461 in complex with MT-2 revealed numerous polar contacts contributing to the nanomolar potency of this compound. Based on the in vitro data on hepcidin regulation, treatment with MI-461 might be valuable in pathological states of iron metabolism without causing excessive oxidative stress.

Regulators of hepcidin expression.

Iron, an essential nutrient, is required for many biological processes but is also toxic in excess. The lack of a mechanism to excrete excess iron makes it crucial for the body to regulate the amount of iron absorbed from the diet. This regulation is mediated by the hepatic hormone hepcidin. Hepcidin also controls iron release from macrophages that recycle iron and from hepatocytes that store iron. Hepcidin binds to the only known iron export protein, ferroportin, inducing its internalization and degradation and thus limiting the amount of iron released into the plasma. Important regulators of hepcidin, and therefore of systemic iron homeostasis, include plasma iron concentrations, body iron stores, infection and inflammation, hypoxia and erythropoiesis, and, to a lesser extent, testosterone. Dysregulation of hepcidin production contributes to the pathogenesis of many iron disorders: hepcidin deficiency causes iron overload in hereditary hemochromatosis and non-transfused β-thalassemia, whereas overproduction of hepcidin is associated with iron-restricted anemias seen in patients with chronic inflammatory diseases and inherited iron-refractory iron-deficiency anemia. The present review summarizes our current understanding of the molecular mechanisms and signaling pathways contributing to hepcidin regulation by these factors and highlights the issues that still need clarification.

Hepcidin and IL-1β.

Hepcidin expression is determined through transcriptional regulation by systemic iron status. However, acute or chronic inflammation also increases the expression of hepcidin, which is associated with the dysregulation of iron metabolism in pathological conditions. Interleukin (IL)-6 has been suggested to be a principal molecule to confer inflammation-related hepcidin transcription, which is mediated via signal transducer and activator of transcription (STAT)-binding site on the hepcidin promoter. Recently, it has been uncovered that another pro-inflammatory cytokine IL-1β stimulates hepcidin expression through the distinct mechanism underlying IL-6-mediated hepcidin transcription. In addition to IL-6 induction, IL-1β stimulates expression of CCAAT-enhancer-binding protein (C/EBP)δ, a transcription factor, leading to transcriptional activation of hepcidin via C/EBP-binding site on the hepcidin promoter. Thus, hepcidin transcription is stimulated through multiple elements in response to proinflammatory cytokines. Relationships between increased production of IL-1β and dysregulated iron metabolism have been suggested in various diseases, which may be linked to overproduction of hepcidin.

Prevalence of Iron Deficiency anemia in Obese Children in Taif Area - Saudi Arabia

Background: The growing global health problem is obesity which has increased dramatically in recent years. The prevalence of obesity continues to rise in developed and developing countries, Poor iron status are affecting millions of people worldwide. Iron deficiency is the first nutrient deficiency all over the world and both obesity and iron deficiency may lead to adverse health issues. In 2013, an estimated 42 million children aged under 5 years (6.3%) were overweight, an increase from around 5% in 2000 to 6% in 2010 and 6.3% in 2013, with the highest rates of increase being observed in Africa and Asia. Rapid changes from traditional to new diets, which contain large amounts of fat, sugar and oil is one of the major causes of obesity. Obesity has been associated with higher rates of death driven by co morbidities. According to the recent researches, the rate of obesity is significantly high in Saudi Arabia, and expected to increase in future. Aim of the study: To evaluate the association between the obesity and iron deficiency anemia among children in Al-Taif Region, Kingdom of Saudi Arabia and to increase the awareness about the hazards of obesity on the general health. Method: A cross sectional study design. A structured questionnaire was designed to obtain the necessary information from a convenient sample of 200 child aging from (5-12 years) attending the pediatric outpatient clinics of pediatric hospital in Taif region - Saudi Arabia from August till November 2016. Information about weight, height, Body Mass Index (BMI), Hemoglobin levels and the serum iron. The assessment of obesity with BMI index using the CDC2000 reference percentile was divided into four categories5th, 50th, 85th and 95th, namely; underweight, normal, overweight and obese respectively. Iron Deficiency was defined as Transferrin Saturation lower than 16% and Iron deficiency anemia was defined as Transferrin Saturation lower than 16% and hemoglobin (Hb) concentration lower than 12 g/l or 12 mg/dl for children. Results: This study shows negative significant correlation between hemoglobin level with the BMI ( r -0.429 p value 0.017 ) delayed weaning & no iron supplements ( r -0.338p value 0.023), bad food habits (r -0.309 p value 0.012) and warm disease, ( r --0.406 p value 0.028), suffering from poor food absorption disease (r 0.266p value 0.033) and chronic diarrhea ( r -0.311p value 0.011) . The prevalence of anemia among the study group shows 60% of its group are suffering from high BMI 79.2% of them suffering from IDA, while 20.8% are healthy. 40% of study group are with normal BMI 21.25% of them are suffering from anemia while 63% are healthy. Conclusions:Hepcidin plays a central role in the anemia of chronic disease and Hepcidin overproduction even in mild inflammatory disorder as obesity may explain the association of poor iron status with obesity. IL6 and Leptin may be part of the axis that links obesity, inflammation, and Hepcidin with poor iron status. This study suggests that the higher levels of total obesity should be taken into account when assessing the children’s body iron status and should be treated before providing dietary recommendations to correct anemia.

Curcuma decreases serum hepcidin levels in healthy volunteers: a placebo-controlled, randomized, double-blind, cross-over study.

Hepcidin, secreted by hepatocytes, controls iron metabolism by limiting iron egress in plasma. Hepcidin is upregulated during inflammation through the activation of the signal transducer and activator of transcription 3 (STAT3) transduction pathway, which decreases iron bioavailability and may explain the anemia of chronic inflammatory disease. In vitro, it has been shown that curcumin can decrease hepcidin synthesis by decreasing STAT3 activity. We conducted a proof-of-concept study to assess the effect of curcuma on hepcidin synthesis in human. This was a placebo-controlled, randomized, double-blind, cross-over, two-period study performed in 18 healthy male volunteers. Subjects received a single oral dose of 6 g curcuma containing 2% of curcumin or placebo. Serum hepcidin and iron parameters were assessed repeatedly until 48 h after dosing. When compared with a placebo curcuma decreased hepcidin levels significantly at 6 h (-19%, P = 0.004), 8 h (-17%, P = 0.009), and 12 h (-17%, P = 0.007) and tended to decrease hepcidin at 24 h (-15%, P = 0.076). Curcuma also significantly increased serum ferritin levels at 6 and 8 h (+7% for both times, P = 0.018, 0.030, respectively) and had no effects on serum iron, transferrin, and transferrin saturation. This pilot study showed that curcuma decreases serum hepcidin levels in human and supports the idea that curcuma could be useful in treating hepcidin overproduction during inflammatory processes. Confirmatory studies in patients with chronic inflammation are now required to determine the optimal dose and therapeutic scheme of curcuma.

Regulation of the Iron Homeostatic Hormone Hepcidin.

Iron is required for many biological processes but is also toxic in excess; thus, body iron balance is maintained through sophisticated regulatory mechanisms. The lack of a regulated iron excretory mechanism means that body iron balance is controlled at the level of absorption from the diet. Iron absorption is regulated by the hepatic peptide hormone hepcidin. Hepcidin also controls iron release from cells that recycle or store iron, thus regulating plasma iron concentrations. Hepcidin exerts its effects through its receptor, the cellular iron exporter ferroportin. Important regulators of hepcidin, and therefore of systemic iron homeostasis, include plasma iron concentrations, body iron stores, infection and inflammation, and erythropoiesis. Disturbances in the regulation of hepcidin contribute to the pathogenesis of many iron disorders: hepcidin deficiency causes iron overload in hereditary hemochromatosis and nontransfused β-thalassemia, whereas overproduction of hepcidin is associated with iron-restricted anemias seen in patients with chronic kidney disease, chronic inflammatory diseases, some cancers, and inherited iron-refractory iron deficiency anemia. This review summarizes our current understanding of the molecular mechanisms and signaling pathways involved in the control of hepcidin synthesis in the liver, a principal determinant of plasma hepcidin concentrations.

Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6-producing lung carcinoma cells.

BackgroundHepcidin, a key regulator of iron metabolism, is produced mainly by interleukin-6 (IL-6) during inflammation. A mechanism linking cancer-related anemia and IL-6 through hepcidin production is suggested. To clarify the hypothesis that overproduction of IL-6 elevates hepcidin levels and contributes to the development of cancer-related anemia, we evaluated anti-IL-6 receptor antibody treatment of cancer-related anemia in an IL-6–producing human lung cancer xenograft model.MethodsNude mice were subcutaneously inoculated with cells of the IL-6–producing human lung cancer cell line LC-06-JCK and assessed as a model of cancer-related anemia. Mice bearing LC-06-JCK were administered rat anti-mouse IL-6 receptor antibody MR16-1 and their serum hepcidin levels and hematological parameters were determined.ResultsLC-06-JCK–bearing mice developed anemia according to the production of human IL-6 from xenografts, with decreased values of hemoglobin, hematocrit, and mean corpuscular volume (MCV) compared to non–tumor-bearing (NTB) mice. LC-06-JCK–bearing mice showed decreased body weight and serum albumin with increased serum amyloid A. MR16-1 treatment showed significant inhibition of decreased body weight and serum albumin levels, and suppressed serum amyloid A level. There was no difference in tumor volume between MR16-1-treated mice and immunoglobulin G (IgG)-treated control mice. Decreased hemoglobin, hematocrit, and MCV in LC-06-JCK–bearing mice was significantly relieved by MR16-1 treatment. LC-06-JCK–bearing mice showed high red blood cell counts and erythropoietin levels as compared to NTB mice, whereas MR16-1 treatment did not affect their levels. Serum hepcidin and ferritin levels were statistically elevated in mice bearing LC-06-JCK. LC-06-JCK–bearing mice showed lower values of MCV, mean corpuscular hemoglobin (MCH), and serum iron as compared to NTB mice. Administration of MR16-1 to mice bearing LC-06-JCK significantly suppressed levels of both serum hepcidin and ferritin, with increased values of MCV and MCH.ConclusionsOur results suggest that overproduction of hepcidin by IL-6 signaling might be a major factor that leads to functionally iron-deficient cancer-related anemia in the LC-06-JCK model. We demonstrated that inhibition of the IL-6 signaling pathway by MR16-1 treatment resulted in significant recovery of iron-deficiency anemia and alleviation of cancer-related symptoms. These results indicate that IL-6 signaling might be one possible target pathway to treat cancer-related anemia disorders.

Hepcidin: a promising marker for differential diagnosis of anemia and macrophage activation syndrome in children with juvenile idiopathic arthritis

Hepcidin is a 25-amino acid peptide, which is a key systemic regulator of iron metabolism. As considered, overproduction of hepcidin in the liver is controlled by high levels of proinflammatory cytokines. Is it known that interleukin-6 play a key role in the development of anemia in patients with juvenile idiopathic arthritis (JIA). However, IL-6 blockers itself may provoke the onset of Macrophage Activation Syndrome (MAS), manifesting, particularly, also with anemia. In view of the fact that macrophages involved in MAS express CD163 - a scavenger receptor that binds hemoglobin-haptoglobin complexes - and activate the pathways which are important for adaptation to oxidative stress induced by free iron, we can consider hepcidin as a welcome challenge to predict the development of MAS early in the course of the disease. During the study of 35 patients with JIA treated with biological disease-modifying drugs (tocilizumab and golimumab), direct relations between the level of hemoglobin and hepcidin were not found. However, it was found that the mean corpuscular hemoglobin level is associated with hepcidin concentration in patients with JIA. It was found that concentration of serum hepcidin may be used for early differential diagnosis of anemia and MAS in patients with JIA. High probability of evolution of anemia to MAS was found when concentration of hepcidin was &lt;140 ng/mL and ferritin &gt;160 g/L. The following combinations were associated with high probability of evolution of slight anemia to a severe form, but not to MAS: 1. hepcidin &gt;200 ng/mL and ferritin &lt;140 g/L; 2. hepcidin &gt;140 ng/mL and soluble transferrin receptor &lt;1.6 mg/L; 3. hepcidin &gt;140 ng/mL and total iron binding capacity &gt;46 mcmol/L. Misclassification should be assessed during further studies.

A critical role for murine transferrin receptor 2 in erythropoiesis during iron restriction.

Effective erythropoiesis requires an appropriate supply of iron and mechanisms regulating iron homeostasis and erythropoiesis are intrinsically linked. Iron dysregulation, typified by iron-deficiency anaemia and iron overload, is common in many clinical conditions and impacts the health of up to 30% of the world's population. The proteins transmembrane protease, serine 6 (TMPRSS6; also termed matriptase-2), HFE and transferrin receptor 2 (TFR2) play important and opposing roles in systemic iron homeostasis, by regulating expression of the iron regulatory hormone hepcidin. We have performed a systematic analysis of mice deficient in these three proteins and show that TMPRSS6 predominates over HFE and TFR2 in hepcidin regulation. The phenotype of mice lacking TMPRSS6 and TFR2 is characterized by severe anaemia and extramedullary haematopoiesis in the spleen. Stress erythropoiesis in these mice results in increased expression of the newly identified erythroid iron regulator erythroferrone, which does not appear to overcome the hepcidin overproduction mediated by loss of TMPRSS6. Extended analysis reveals that TFR2 plays an important role in erythroid cells, where it is involved in terminal erythroblast differentiation and the regulation of erythropoietin. In conclusion, we have identified an essential role for TFR2 in erythropoiesis that may provide new targets for the treatment of anaemia.

Anemia in children with JIA: is it really driven by hepcidin level, or by a set of factors of a chronic disease

Hepcidin - 25-amino acid peptide - is known to be a key regulator of systemic iron metabolism [Ganz T., Nemeth E., 2012]. Hepcidin acts indirectly through ferroportin, which is both a receptor for hepcidin and the only known exporter of iron in the human body [De Falco L. et. al., 2013]. Hyperproduction of hepcidin due to the influence of pro-inflammatory cytokines, especially IL-6, triggers to transport of iron from circulation to the storage, consequently, limiting iron accessibility for erythropoiesis [Weiss G., Goodnought T., 2005]. Thus, overproduction of hepcidin seems to be the leading mechanism of development of anemia in children with Juvenile Idiopathic Arthritis (JIA). A set of negative factors of a chronic disease, particularly disbalance of vitamins, proteins, amino acids and minerals, which are also the known causes, of anemia can weaken control of iron metabolism by hepcidin.

LY2928057, An Antibody Targeting Ferroportin, Is a Potent Inhibitor Of Hepcidin Activity and Increases Iron Mobilization In Normal Cynomolgus Monkeys

Hepcidin, a 25-amino acid peptide hormone which is primarily synthesized and secreted from the liver, is a key regulator of iron homeostasis. It regulates dietary iron absorption, plasma iron concentrations, and tissue iron distribution through interactions with ferroportin, the only known mammalian cellular iron exporter. Hepcidin induces the internalization and subsequent degradation of ferroportin. The reduction in iron release caused by the loss of ferroportin, combined with the continuing demand for iron by erythropoietic precursors, results in a decrease in circulating iron levels. Dysregulation of the hepcidin-ferroportin axis contributes to the pathogenesis of different anemias. Decreased synthesis of hepcidin may cause systemic iron overload in iron-loading anemias such as beta-thalassemia; whereas overproduction of hepcidin may contribute to the development of anemia in inflammatory disorders, malignancies, and chronic kidney disease. LY2928057 is a novel humanized IgG4 monoclonal antibody that binds to human ferroportin with a high affinity, blocks the binding of human hepcidin to ferroportin, and is a potent inhibitor of hepcidin activity in a recombinant ferroportin expressing HEK 293 cell-based assay. In addition, this antibody was able to significantly inhibit hepcidin-induced increase in ferritin levels using Caco-2 cells, a human enterocyte cell line that naturally expresses ferroportin. LY2928057 does not block the efflux of iron from ferroportin, nor does this antibody cause the internalization of this transporter in vitro. Administration of LY2928057 results in a dose dependent increase in serum iron and hepcidin in normal cynomolgus monkeys. LY2928057 may provide therapeutic benefit for patients with hepcidin-related anemia by stabilizing ferroportin located on the cell surface, thus restoring iron export and erythropoiesis. LY2928057 is currently in clinical evaluation. Disclosures:Witcher:Eli Lilly and Company: Employment, Equity Ownership. Leung:Eli Lilly and Company: Employment, Equity Ownership. Hill:Eli Lilly and Company: Employment, Equity Ownership. De Rosa:Eli Lilly and Company: Employment, Equity Ownership. Xu:Eli Lilly and Company: Employment, Equity Ownership. Manetta:Eli Lilly and Company: Employment, Equity Ownership. Wroblewski:Eli Lilly and Company: Employment, Equity Ownership. Benschop:Eli Lilly and Company: Employment, Equity Ownership.

Hepcidin Is Produced by Lymphoplasmacytic Cells and Is Associated With Anemia in Waldenström's Macroglobulinemia

Waldenström's macroglobulinemia (WM) patients often present with anemia as their primary disease manifestation that may be related to hepcidin, an important regulator of iron homeostasis. We therefore determined hepcidin levels in 53 WM patients, and 20 age-matched healthy patient donors by hepcidin-25 ELISA. Serum hepcidin levels were elevated in WM patients versus healthy patients (P=.04), and correlated with BM disease involvement (P=.004), beta-2-microglobulin levels (P=.029), and inversely with hemoglobin (P=.05). No correlation with serum iron indices was observed, though in patients with high hepcidin levels, increased iron deposition in bone marrow macrophages was observed. Importantly, hepcidin transcripts and protein were produced by primary WM cells. Hepcidin levels correlated with serum IL-6 (P<.001) and C-Reactive Protein (P=.033) levels. The results of this study implicate hepcidin as a contributor to anemia in WM, and suggest that an iron re-utilization defect accompanies hepcidin overproduction leading to its sequestration in WM patients.

Hepcidin independent anemia of inflammation

Because hepcidin overproduction mimics anemia of inflammation and absence of hepcidin protects against the acute hypoferremia seen in response to inflammation, hepcidin is presumed to be necessary for the development of anemia of inflammation (AI, anemia of chronic disease). However no independent studies have tested this hypothesis. Using two mouse models of anemia of inflammation and hepcidin deficient mice, we sought to determine whether hepcidin is necessary for the development of anemia of inflammation. Hepcidin knockout mice maintained on a standard iron diet were largely protected against AI. However, these mice have severe iron overload prior to the onset of inflammation, which may protect them against AI. We therefore sought to prevent the development of iron overload prior to the onset of inflammation by restricting dietary iron immediately after weaning. Hepcidin knockout mice without baseline iron overload developed anemia as severe as wild type mice and this anemia was iron restricted. Therefore, hepcidin is not necessary for the development of anemia in some inflammatory diseases. Hepcidin antagonists may not be effective in treating some patients with AI.

Biting the Iron Bullet: Endoplasmic Reticulum Stress Adds the Pain of Hepcidin to Chronic Liver Disease

Abstract Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element-binding protein H), an ER stress-activated transcription factor, binds to and transactivates the hepcidin promoter. Hepcidin induction in response to exogenously administered toxins or accumulation of unfolded protein in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress-regulated hepcidin expression. The regulation of hepcidin by ER stress links the intracellular response involved in protein quality control to innate immunity and iron homeostasis.

Oncostatin M and leukemia inhibitory factor increase hepcidin expression in hepatoma cell lines

Overproduction of hepcidin by interleukin-6 (IL-6) is considered to be the main factor responsible for the development of anemia in inflammatory conditions. Since oncostatin M (OSM), a member of the IL-6 family, plays an important role in immune and inflammatory responses, we assessed the effect of OSM on hepcidin expression, as well as that of leukemia inhibitory factor (LIF), another member of the IL-6 family. We found that hepcidin expression was markedly induced by OSM and LIF in a time- and dose-dependent manner in hepatoma cell lines, and this expression was induced independent of IL-6/IL-6 receptor signaling. Luciferase assay revealed that OSM and LIF stimulated a -1.3-kb hepcidin promoter. This effect was markedly reduced when the signal transducer and activator of transcription (STAT) site of the promoter was mutated, and was almost completely abolished in the presence of AG-490, a Janus kinase (JAK) inhibitor. Hence, the JAK/STAT pathway plays a major role in OSM- and LIF-induced activation of the hepcidin promoter. In conclusion, we demonstrated that OSM and LIF can induce hepcidin expression mainly through the JAK/STAT pathways. Further studies are warranted to evaluate the clinical significance of OSM and LIF in the development of anemia in various inflammatory diseases.

ER stress controls iron metabolism through induction of hepcidin.

Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element-binding protein H), an ER stress-activated transcription factor, binds to and transactivates the hepcidin promoter. Hepcidin induction in response to exogenously administered toxins or accumulation of unfolded protein in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress-regulated hepcidin expression. The regulation of hepcidin by ER stress links the intracellular response involved in protein quality control to innate immunity and iron homeostasis.