SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on November 14, 2002; DOI 10.1182/blood-2002-10-3235. This Article Abstract Full Text (PDF) All Versions of this Article: 2002-10-3235v1 101/7/2461    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nemeth, E. Articles by Ganz, T. Search for Related Content PubMed PubMed Citation Articles by Nemeth, E. Articles by Ganz, T. Related Collections Red Cells Plenary Papers Gene Expression Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 April 2003, Vol. 101, No. 7, pp. 2461-2463 PLENARY PAPERS Brief report Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein Elizabeta Nemeth, Erika V. Valore, Mary Territo, Gary Schiller, Alan Lichtenstein, and Tomas Ganz From the Departments of Medicine and Pathology, David Geffen School of Medicine, and the West Los Angeles Veterans Administration Hospital, University of California, Los Angeles (UCLA), Los Angeles, CA.     Abstract Top Abstract Introduction Study design Results and discussion References Hepcidin is a liver-made peptide proposed to be a central regulator of intestinal iron absorption and iron recycling by macrophages. In animal models, hepcidin is induced by inflammation and iron loading, but its regulation in humans has not been studied. We report that urinary excretion of hepcidin was greatly increased in patients with iron overload, infections, or inflammatory diseases. Hepcidin excretion correlated well with serum ferritin levels, which are regulated by similar pathologic stimuli. In vitro iron loading of primary human hepatocytes, however, unexpectedly down-regulated hepcidin mRNA, suggesting that in vivo regulation of hepcidin expression by iron stores involves complex indirect effects. Hepcidin mRNA was dramatically induced by interleukin-6 (IL-6) in vitro, but not by IL-1 or tumor necrosis factor  (TNF-), demonstrating that human hepcidin is a type II acute-phase reactant. The linkage of hepcidin induction to inflammation in humans supports its proposed role as a key mediator of anemia of inflammation. (Blood. 2003;101:2461-2463) © 2003 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References The recently discovered peptide hepcidin1 may be the key mediator of anemia of inflammation.2,3 It is a conserved 25-amino acid peptide produced in the liver and detectable in blood and urine.1,4 Mice lacking hepcidin mRNA developed iron overload affecting the liver and pancreas, with iron deficit in the macrophage-rich spleen.5 Transgenic mice overexpressing hepcidin died at birth of severe iron deficiency.6 These studies suggested that hepcidin inhibits iron absorption in the small intestine, the release of recycled iron from macrophages,2 and transport of iron across the placenta.6 In agreement with the animal studies, patients with large hepatic adenomas and otherwise unexplained iron-refractory anemia overexpressed hepcidin mRNA in their tumors.3 Studies of hepcidin mRNA regulation showed increase in iron-overloaded mice7 and decrease in mice with anemia from bleeding or hemolysis.8 Mice injected with lipopolysaccharide7 or turpentine,8 and fish with bacterial infection9 also had elevated hepcidin mRNA in the liver. Together, the data suggest hepcidin is induced by iron stores and inflammation, and functions as a signal inhibiting iron absorption in the small intestine and sequestering iron in macrophages.2 However, all findings on hepcidin regulation have come from animal models. We explored the regulation of hepcidin synthesis in human patients and tissues.     Study design Top Abstract Introduction Study design Results and discussion References Subjects Approval was obtained from the UCLA institutional review board for these studies. Informed consent was provided according to the Declaration of Helsinki. The patients' total iron-binding capacity (TIBC), and levels of serum iron, ferritin, hemoglobin, hematocrit, and urinary creatinine were determined at the UCLA Hospital Laboratory. Reagents Hepcidin antibody was prepared by rabbit immunization with synthetic hepcidin1 conjugated to keyhole limpet hemocyanin (KLH, no. 7762; Pierce, Rockford, IL). Urinary hepcidin assay Cationic peptides were extracted from urine using CM Macroprep (Bio-Rad, Hercules, CA).1 Urine extracts equivalent to 4 mg of creatinine were analyzed along with synthetic hepcidin standards (0.05, 0.15, 0.5, and 1.5 µg) by sodium dodecyl sulfate (SDS)-Tricine-polyacrylamide gel electrophoresis (PAGE) and Western blotting. Hepcidin was detected on the blots using rabbit antihuman hepcidin antibody. Hepatocyte culture Human hepatocytes (Liver Tissue Procurement and Distribution System, Minneapolis, MN) were cultured in human hepatocyte maintenance medium (Clonetics, San Diego, CA) at 37°C, 5% CO2. Hepatocyte treatments included 10 µM ferric-ammonium citrate (FAC; Sigma, St Louis, MO), 30 µM diferric transferrin (Sigma), 20 ng/mL interleukin-1 (IL-1; R&D Systems, Minneapolis, MN), 20 ng/mL IL-6 (PeproTech, Rocky Hill, NJ), 20 ng/mL tumor necrosis factor  (TNF-; R&D Systems), 100 ng/mL lipopolysaccharide (LPS; Escherichia coli 055:B5), medium conditioned by monocytes incubated with LPS (Mo-LPS; final concentration 12.5%), and 200 ng/mL IL-1 receptor antagonist (R&D Systems). Monocyte culture Blood monocytes were isolated by centrifugation at 400g for 20 minutes through Ficoll-Paque (Amersham Pharmacia Biotech, Piscataway, NJ) and at 550g for 30 minutes in 46% isoosmotic Percoll (Sigma) gradient. Monocyte purity was 80% by Wright stain. Monocytes were cultured at 1 × 106/mL in Iscove modified Dulbecco medium supplemented with 10% fetal bovine serum and 20% autologous serum. The Mo-LPS conditioned medium (CM) was prepared by incubating monocytes with LPS for 4 days and collecting the cell-free supernatant. RNA isolation and Northern blot analysis Hepatocyte RNA was prepared using TRIzol reagent (Invitrogen, Carlsbad, CA). Total RNA (15 µg per lane) was separated on a 1% agarose formaldehyde gel, transferred, and ultraviolet (UV) light-crosslinked. Hepcidin probe (173-base pair [bp]) was generated by polymerase chain reaction (PCR).1 A 218-bp probe for ferritin heavy chain was generated by reverse transcriptase (RT)-PCR from hepatic RNA with the following primers: forward, 5'-CTGTCCATGTCTTACTACTTTGACC-3' and reverse, 5'-TCCAAATGTAATGCACACTCC-3'. Hybridization was performed at 42°C in Ultrahybe (Ambion, Austin, TX) with random-primed, 32P-labeled cDNA probes for hepcidin, ferritin, and glyceraldehyde-3-phosphate dehydrogenase (G3PD).     Results and discussion Top Abstract Introduction Study design Results and discussion References Patients with anemia of inflammation, diagnosed by elevated serum ferritin and compatible clinical history, had elevated urinary hepcidin excretion compared with healthy subjects and patients with iron deficiency anemia or well-controlled hereditary hemochromatosis (Figure 1A). Patients with transfusion-induced iron overload (2 sickle-cell anemia, 1 myelodysplasia) identified by compatible clinical history, Fe/TIBC higher than 50% and ferritin levels higher than 300 ng/mL, also showed greatly increased urinary hepcidin. Urinary hepcidin excretion correlated with serum ferritin levels (R2 = 0.69, Figure 1B). In a patient with epididymitis and sepsis (Figure 1C), Western blotting showed very high urinary hepcidin excretion on day 1 (1.5 mg/d), which gradually decreased over a period of days to undetectable levels (day 25) as the infection resolved with treatment. Because of its small size (approximately 2 kDa) and disulfide crosslinking,10 hepcidin is expected to be filtered into the urine, where it apparently escapes tubular proteolysis and recycling. Unless circulating hepcidin is variably degraded by as yet unknown metabolic pathways, its urinary excretion should closely reflect production rates. This is the first direct evidence that infection and inflammation induce hepcidin production in humans. View larger version (13K): [in this window] [in a new window]   Figure 1. Hepcidin excretion is increased in patients with anemia of inflammation, iron overload, or infection. (A) Urinary hepcidin excretion in patients with anemia of inflammation (AI, ), iron overload (IO, ), compensated hereditary hemochromatosis (HH-C, ), and iron deficiency anemia (IDA, ); urinary hepcidin excretion in healthy donors (NL, ). (B) Urinary hepcidin excretion in the same patients and its correlation with serum ferritin. (C) Urinary hepcidin excretion in response to acute infection in a single donor with epididymitis and sepsis, treated with antibiotics from day 1. Dotted line indicates detection limit. Creat indicates creatinine. We next explored the molecular basis of hepcidin regulation in primary human hepatocytes. These were incubated either in serum-free medium, or with 10% fetal calf serum (FCS), with iron loading or inflammatory stimuli (Figure 2A). Surprisingly, iron loading of hepatocytes resulted in a 50% decrease in hepcidin mRNA. When higher concentrations of iron were used (up to 10 mM, not shown), hepcidin mRNA decreased even more. In contrast, ferritin H expression increased with higher doses of iron (not shown). Since hepcidin expression was induced in mice fed or injected with iron,7 our data raise the possibility that other iron-sensing cells signal to hepatocytes to induce the production of hepcidin during iron overload. An indirect link between iron and hepcidin induction in hepatocytes is also supported by studies in a mouse model of anemia where hepcidin mRNA was down-regulated in the liver, despite normal or even increased hepatic iron.8 View larger version (31K): [in this window] [in a new window]   Figure 2. Hepcidin mRNA is induced by IL-6. Northern blots of human hepatocyte RNA were probed for hepcidin, ferritin H, and glyceraldehyde-3-phosphate-dehydrogenase (G3PD) mRNAs. (A) Hepatocytes were treated for 24 hours in the presence or absence of 10% FCS, with serum-free medium (0), ferric ammonium citrate (FAC), iron-saturated ferritin (Fe-Tf), lipopolysaccharide (LPS), 12.5% monocyte medium + LPS (M+LPS), and 12.5% monocyte medium conditioned by monocytes exposed to LPS (Mo-LPS). (B) Hepatocytes were treated for the indicated time with cytokines or Mo-LPS (12.5% monocyte medium conditioned by monocytes exposed to LPS), without or with IL-1 receptor antagonist (IL-1Ra). Treatment of hepatocytes with Mo-LPS CM increased hepcidin mRNA up to 25-fold, but LPS alone caused only a small (2- to 3-fold) increase (Figure 2B). Monocytes/macrophages exposed to LPS secrete cytokines that mediate acute-phase response. Of the 2 major patterns of acute-phase response in hepatocytes,11,12 type I response is induced by IL-1-like cytokines (IL-1, IL-1, TNF-, and TNF-) and increases the production of serum amyloid A, C-reactive protein, and complement C3; whereas type II response is induced by IL-6-like cytokines and results in increased synthesis of fibrinogen, haptoglobin, and 1-antitrypsin. Hepcidin was induced within 8 hours by IL-6 (25-fold) and Mo-LPS CM, but not by IL-1 or TNF-, indicating that induction of hepcidin is a type II acute-phase response. After 24 hours of cytokine treatment, hepcidin mRNA was also induced by IL-1, but this was probably an indirect effect of IL-1 via induction of IL-6 synthesis in hepatocytes. Also, addition of IL-1 receptor antagonist to LPS-conditioned monocyte medium did not reduce hepcidin expression, supporting the finding that IL-1 is not an important direct mediator of hepcidin induction. Ferritin H mRNA showed a weak type I pattern of induction in hepatocytes: IL-1 and TNF-, but not IL-6, increased ferritin mRNA, and addition of IL-1Ra to Mo-LPS CM decreased ferritin mRNA. Although measurements of urinary hepcidin and serum ferritin correlate in patients with different iron disorders, and although both are shown to be regulated by iron and inflammation,7,8,13 the respective molecular pathways regulating their expression appear to be distinct. Hepcidin is thus a type II acute-phase protein that provides a molecular link between inflammation, resulting anemia, and the regulation of iron metabolism. Additional studies will be necessary to explain the mechanism of hepcidin effect on iron transport and the more complex indirect effects that appear to mediate the regulation of hepcidin production by iron stores.     Acknowledgments We thank Audrea Troutman for her contribution to this project, Lide Liu for advice and reagents, and Stephen Strom for providing human hepatocytes and advice.     Footnotes Submitted October 25, 2002; accepted November 5, 2002. Prepublished online as Blood First Edition Paper, November 14, 2002; DOI 10.1182/blood-2002-10-3235. Supported by the Will Rogers Fund (T.G.). The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Tomas Ganz, 37-055 CHS, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1690; e-mail: tganz{at}mednet.ucla.edu.     References Top Abstract Introduction Study design Results and discussion References 1. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806-7810[Abstract/Free Full Text]. 2. Fleming RE, Sly WS. Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci U S A. 2001;98:8160-8162[Free Full Text]. 3. Weinstein DA, Roy CN, Fleming MD, et al. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;2002-2004. 4. Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480:147-150[CrossRef][Medline] [Order article via Infotrieve]. 5. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A. 2001;98:8780-8785[Abstract/Free Full Text]. 6. Nicolas G, Bennoun M, Porteu A, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A. 2002;99:4596-4601[Abstract/Free Full Text]. 7. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276:7811-7819[Abstract/Free Full Text]. 8. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037-1044[Abstract/Free Full Text]. 9. Shike H, Lauth X, Westerman ME, et al. Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge. Eur J Biochem. 2002;269:2232-2237[Abstract/Free Full Text]. 10. Hunter HN, Fulton DB, Ganz T, Vogel HJ. The solution structure of human hepcidin, a peptide-hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002;277:37597-37603[Abstract/Free Full Text]. 11. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448-454[Free Full Text]. 12. Moshage H. Cytokines and the hepatic acute phase response. J Pathol. 1997;181:257-266[CrossRef][Medline] [Order article via Infotrieve]. 13. Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood. 2002;99:3505-3516[Free Full Text]. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. B. Sow, G. R. Alvarez, R. P. Gross, A. R. Satoskar, L. S. Schlesinger, B. S. Zwilling, and W. P. Lafuse Role of STAT1, NF-{kappa}B, and C/EBP{beta} in the macrophage transcriptional regulation of hepcidin by mycobacterial infection and IFN-{gamma} J. Leukoc. Biol., November 1, 2009; 86(5): 1247 - 1258. [Abstract] [Full Text] [PDF] P. Schwarz, P. Strnad, N. Singer, F. Oswald, R. Ehehalt, G. Adler, and H. Kulaksiz Identification, sequencing, and cellular localization of hepcidin in guinea pig (Cavia porcellus) J. Endocrinol., September 1, 2009; 202(3): 389 - 396. [Abstract] [Full Text] [PDF] M. Andreani, F. C. Radio, M. Testi, C. De Bernardo, M. Troiano, S. Majore, P. Bertucci, P. Polchi, R. Rosati, and P. Grammatico Association of hepcidin promoter c.-582 A>G variant and iron overload in thalassemia major Haematologica, September 1, 2009; 94(9): 1293 - 1296. [Abstract] [Full Text] [PDF] C. Vecchi, G. Montosi, K. Zhang, I. Lamberti, S. A. Duncan, R. J. Kaufman, and A. Pietrangelo ER Stress Controls Iron Metabolism Through Induction of Hepcidin Science, August 14, 2009; 325(5942): 877 - 880. [Abstract] [Full Text] [PDF] L. Ukarma, H. Johannes, U. Beyer, M. Zaug, B. Osterwalder, and A. Scherhag Hepcidin as a Predictor of Response to Epoetin Therapy in Anemic Cancer Patients Clin. Chem., July 1, 2009; 55(7): 1354 - 1360. [Abstract] [Full Text] [PDF] P. Robach, S. Recalcati, D. Girelli, C. Gelfi, N. J. Aachmann-Andersen, J. J. Thomsen, A. M. Norgaard, A. Alberghini, N. Campostrini, A. Castagna, et al. Alterations of systemic and muscle iron metabolism in human subjects treated with low-dose recombinant erythropoietin Blood, June 25, 2009; 113(26): 6707 - 6715. [Abstract] [Full Text] [PDF] F. Marques, A. M. Falcao, J. C. Sousa, G. Coppola, D. Geschwind, N. Sousa, M. Correia-Neves, and J. A. Palha Altered Iron Metabolism Is Part of the Choroid Plexus Response to Peripheral Inflammation Endocrinology, June 1, 2009; 150(6): 2822 - 2828. [Abstract] [Full Text] [PDF] J. Zaritsky, B. Young, H.-J. Wang, M. Westerman, G. Olbina, E. Nemeth, T. Ganz, S. Rivera, A. R. Nissenson, and I. B. Salusky Hepcidin--A Potential Novel Biomarker for Iron Status in Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., June 1, 2009; 4(6): 1051 - 1056. [Abstract] [Full Text] [PDF] P. Matak, T. B. Chaston, B. Chung, S. K. Srai, A. T. McKie, and P. A. Sharp Activated macrophages induce hepcidin expression in HuH7 hepatoma cells Haematologica, June 1, 2009; 94(6): 773 - 780. [Abstract] [Full Text] [PDF] G. Ramey, J.-C. Deschemin, and S. Vaulont Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes Haematologica, June 1, 2009; 94(6): 765 - 772. [Abstract] [Full Text] [PDF] S. Soe-Lin, S. S. Apte, B. Andriopoulos Jr., M. C. Andrews, M. Schranzhofer, T. Kahawita, D. Garcia-Santos, and P. Ponka Nramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo PNAS, April 7, 2009; 106(14): 5960 - 5965. [Abstract] [Full Text] [PDF] S. A. Browne and D. Reddan Potential role of bone morphogenetic protein (BMP) signalling as a potential therapeutic target for modification of iron balance Nephrol. Dial. Transplant., January 1, 2009; 24(1): 28 - 30. [Full Text] [PDF] T. Ganz, G. Olbina, D. Girelli, E. Nemeth, and M. Westerman Immunoassay for human serum hepcidin Blood, November 15, 2008; 112(10): 4292 - 4297. [Abstract] [Full Text] [PDF] N Scamuffa, A Basak, C Lalou, A Wargnier, J Marcinkiewicz, G Siegfried, M Chretien, F Calvo, N G Seidah, and A-M Khatib Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7 Gut, November 1, 2008; 57(11): 1573 - 1582. [Abstract] [Full Text] [PDF] J. F. Collins, M. Wessling-Resnick, and M. D. Knutson Hepcidin Regulation of Iron Transport J. Nutr., November 1, 2008; 138(11): 2284 - 2288. [Abstract] [Full Text] [PDF] P Emery, E Keystone, H P Tony, A Cantagrel, R van Vollenhoven, A Sanchez, E Alecock, J Lee, and J Kremer IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial Ann Rheum Dis, November 1, 2008; 67(11): 1516 - 1523. [Abstract] [Full Text] [PDF] W. H. Horl New insights into intestinal iron absorption Nephrol. Dial. Transplant., October 1, 2008; 23(10): 3063 - 3064. [Full Text] [PDF] K. C. Sihler and L. M. Napolitano Anemia of Inflammation in Critically Ill Patients J Intensive Care Med, September 1, 2008; 23(5): 295 - 302. [Abstract] [PDF] D. W. Swinkels and J. F. M. Wetzels Hepcidin: a new tool in the management of anaemia in patients with chronic kidney disease? Nephrol. Dial. Transplant., August 1, 2008; 23(8): 2450 - 2453. [Full Text] [PDF] Q. Wang, F. Du, Z.-M. Qian, X. H. Ge, L. Zhu, W. H. Yung, L. Yang, and Y. Ke Lipopolysaccharide Induces a Significant Increase in Expression of Iron Regulatory Hormone Hepcidin in the Cortex and Substantia Nigra in Rat Brain Endocrinology, August 1, 2008; 149(8): 3920 - 3925. [Abstract] [Full Text] [PDF] P. N. Paradkar, I. De Domenico, N. Durchfort, I. Zohn, J. Kaplan, and D. M. Ward Iron depletion limits intracellular bacterial growth in macrophages Blood, August 1, 2008; 112(3): 866 - 874. [Abstract] [Full Text] [PDF] N. C. Andrews Forging a field: the golden age of iron biology Blood, July 15, 2008; 112(2): 219 - 230. [Full Text] [PDF] S. Sharma, E. Nemeth, Y.-H. Chen, J. Goodnough, A. Huston, G.D. Roodman, T. Ganz, and A. Lichtenstein Involvement of Hepcidin in the Anemia of Multiple Myeloma Clin. Cancer Res., June 1, 2008; 14(11): 3262 - 3267. [Abstract] [Full Text] [PDF] X. Du, E. She, T. Gelbart, J. Truksa, P. Lee, Y. Xia, K. Khovananth, S. Mudd, N. Mann, E. M. Y. Moresco, et al. The Serine Protease TMPRSS6 Is Required to Sense Iron Deficiency Science, May 23, 2008; 320(5879): 1088 - 1092. [Abstract] [Full Text] [PDF] S. Liu, R. N.V.S. Suragani, A. Han, W. Zhao, N. C. Andrews, and J.-J. Chen Deficiency of heme-regulated eIF2{alpha} kinase decreases hepcidin expression and splenic iron in HFE-/- mice Haematologica, May 1, 2008; 93(5): 753 - 756. [Abstract] [Full Text] [PDF] S. A. Bloomer, K. E. Brown, G. R. Buettner, and K. C. Kregel Dysregulation of hepatic iron with aging: implications for heat stress-induced oxidative liver injury Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2008; 294(4): R1165 - R1174. [Abstract] [Full Text] [PDF] G. Weiss and I. Theurl Response: Monocyte hepcidin and the anemia of chronic disease Blood, April 1, 2008; 111(7): 3902 - 3903. [Full Text] [PDF] I. Theurl, M. Theurl, M. Seifert, S. Mair, M. Nairz, H. Rumpold, H. Zoller, R. Bellmann-Weiler, H. Niederegger, H. Talasz, et al. Autocrine formation of hepcidin induces iron retention in human monocytes Blood, February 15, 2008; 111(4): 2392 - 2399. [Abstract] [Full Text] [PDF] A. L. Lagan, D. D. Melley, T. W. Evans, and G. J. Quinlan Pathogenesis of the systemic inflammatory syndrome and acute lung injury: role of iron mobilization and decompartmentalization Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L161 - L174. [Abstract] [Full Text] [PDF] E. H.J.M. Kemna, H. Tjalsma, H. L. Willems, and D. W. Swinkels Hepcidin: from discovery to differential diagnosis Haematologica, January 1, 2008; 93(1): 90 - 97. [Abstract] [Full Text] [PDF] E. Camberlein, G. Zanninelli, L. Detivaud, A. R. Lizzi, F. Sorrentino, S. Vacquer, M.-B. Troadec, E. Angelucci, E. Abgueguen, O. Loreal, et al. Anemia in -thalassemia patients targets hepatic hepcidin transcript levels independently of iron metabolism genes controlling hepcidin expression Haematologica, January 1, 2008; 93(1): 111 - 115. [Abstract] [Full Text] [PDF] M. D. Fleming The Regulation of Hepcidin and Its Effects on Systemic and Cellular Iron Metabolism Hematology, January 1, 2008; 2008(1): 151 - 158. [Abstract] [Full Text] [PDF] A. Piperno, D. Girelli, E. Nemeth, P. Trombini, C. Bozzini, E. Poggiali, Y. Phung, T. Ganz, and C. Camaschella Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis Blood, December 1, 2007; 110(12): 4096 - 4100. [Abstract] [Full Text] [PDF] B. Chung, P. Matak, A. T. McKie, and P. Sharp Leptin Increases the Expression of the Iron Regulatory Hormone Hepcidin in HuH7 Human Hepatoma Cells J. Nutr., November 1, 2007; 137(11): 2366 - 2370. [Abstract] [Full Text] [PDF] F. B. Sow, W. C. Florence, A. R. Satoskar, L. S. Schlesinger, B. S. Zwilling, and W. P. Lafuse Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis J. Leukoc. Biol., October 1, 2007; 82(4): 934 - 945. [Abstract] [Full Text] [PDF] P. Trombini, T. Coliva, E. Nemeth, R. Mariani, T. Ganz, A. Biondi, and A. Piperno Effects of plasma transfusion on hepcidin production in human congenital hypotransferrinemia Haematologica, October 1, 2007; 92(10): 1407 - 1410. [Abstract] [Full Text] [PDF] L. Lin, E. V. Valore, E. Nemeth, J. B. Goodnough, V. Gabayan, and T. Ganz Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4 Blood, September 15, 2007; 110(6): 2182 - 2189. [Abstract] [Full Text] [PDF] A. T. Murphy, D. R. Witcher, P. Luan, and V. J. Wroblewski Quantitation of hepcidin from human and mouse serum using liquid chromatography tandem mass spectrometry Blood, August 1, 2007; 110(3): 1048 - 1054. [Abstract] [Full Text] [PDF] A. A. Lamikanra, D. Brown, A. Potocnik, C. Casals-Pascual, J. Langhorne, and D. J. Roberts Malarial anemia: of mice and men Blood, July 1, 2007; 110(1): 18 - 28. [Abstract] [Full Text] [PDF] H. Kawabata, N. Tomosugi, J. Kanda, Y. Tanaka, K. Yoshizaki, and T. Uchiyama Anti-interleukin 6 receptor antibody tocilizumab reduces the level of serum hepcidin in patients with multicentric Castleman's disease Haematologica, June 1, 2007; 92(6): 857 - 858. [Abstract] [Full Text] [PDF] U. Merle, E. Fein, S. G. Gehrke, W. Stremmel, and H. Kulaksiz The Iron Regulatory Peptide Hepcidin Is Expressed in the Heart and Regulated by Hypoxia and Inflammation Endocrinology, June 1, 2007; 148(6): 2663 - 2668. [Abstract] [Full Text] [PDF] K. A. Zarember, J. A. Sugui, Y. C. Chang, K. J. Kwon-Chung, and J. I. Gallin Human Polymorphonuclear Leukocytes Inhibit Aspergillus fumigatus Conidial Growth by Lactoferrin-Mediated Iron Depletion J. Immunol., May 15, 2007; 178(10): 6367 - 6373. [Abstract] [Full Text] [PDF] C. N. Roy, H. H. Mak, I. Akpan, G. Losyev, D. Zurakowski, and N. C. Andrews Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation Blood, May 1, 2007; 109(9): 4038 - 4044. [Abstract] [Full Text] [PDF] E. H.J.M. Kemna, H. Tjalsma, V. N. Podust, and D. W. Swinkels Mass Spectrometry-Based Hepcidin Measurements in Serum and Urine: Analytical Aspects and Clinical Implications Clin. Chem., April 1, 2007; 53(4): 620 - 628. [Abstract] [Full Text] [PDF] J. M. Fernandez-Real, J. M. Moreno, B. Chico, A. Lopez-Bermejo, and W. Ricart Circulating Visfatin Is Associated With Parameters of Iron Metabolism in Subjects With Altered Glucose Tolerance Diabetes Care, March 1, 2007; 30(3): 616 - 621. [Abstract] [Full Text] [PDF] M. Constante, D. Wang, V.-A. Raymond, M. Bilodeau, and M. M. Santos Repression of Repulsive Guidance Molecule C during Inflammation Is Independent of Hfe and Involves Tumor Necrosis Factor-{alpha} Am. J. Pathol., February 1, 2007; 170(2): 497 - 504. [Abstract] [Full Text] [PDF] T. Ganz Molecular Control of Iron Transport J. Am. Soc. Nephrol., February 1, 2007; 18(2): 394 - 400. [Abstract] [Full Text] [PDF] M. V. Verga Falzacappa, M. Vujic Spasic, R. Kessler, J. Stolte, M. W. Hentze, and M. U. Muckenthaler STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation Blood, January 1, 2007; 109(1): 353 - 358. [Abstract] [Full Text] [PDF] H. K. Bayele, H. McArdle, and S. K.S. Srai Cis and trans regulation of hepcidin expression by upstream stimulatory factor Blood, December 15, 2006; 108(13): 4237 - 4245. [Abstract] [Full Text] [PDF] F. I. Haurani Hepcidin and the anemia of chronic disease. Ann. Clin. Lab. Sci., December 1, 2006; 36(1): 3 - 6. [Full Text] [PDF] H. Christiansen, N. Sheikh, B. Saile, F. Reuter, M. Rave-Frank, R. M. Hermann, J. Dudas, A. Hille, C. F. Hess, and G. Ramadori x-Irradiation in Rat Liver: Consequent Upregulation of Hepcidin and Downregulation of Hemojuvelin and Ferroportin-1 Gene Expression Radiology, December 1, 2006; 242(1): 189 - 197. [Abstract] [Full Text] [PDF] M. Pak, M. A. Lopez, V. Gabayan, T. Ganz, and S. Rivera Suppression of hepcidin during anemia requires erythropoietic activity Blood, December 1, 2006; 108(12): 3730 - 3735. [Abstract] [Full Text] [PDF] D. M. Wrighting and N. C. Andrews Interleukin-6 induces hepcidin expression through STAT3 Blood, November 1, 2006; 108(9): 3204 - 3209. [Abstract] [Full Text] [PDF] M. L Rise, S. E Douglas, D. Sakhrani, J. Williams, K V. Ewart, M. Rise, W. S Davidson, B. F Koop, and R. H Devlin Multiple microarray platforms utilized for hepatic gene expression profiling of GH transgenic coho salmon with and without ration restriction. J. Mol. Endocrinol., October 1, 2006; 37(2): 259 - 282. [Abstract] [Full Text] [PDF] N.-B. Nguyen, K. D. Callaghan, A. J. Ghio, D. J. Haile, and F. Yang Hepcidin expression and iron transport in alveolar macrophages Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L417 - L425. [Abstract] [Full Text] [PDF] J.-C. Lesbordes-Brion, L. Viatte, M. Bennoun, D.-Q. Lou, G. Ramey, C. Houbron, G. Hamard, A. Kahn, and S. Vaulont Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis Blood, August 15, 2006; 108(4): 1402 - 1405. [Abstract] [Full Text] [PDF] N. Tomosugi, H. Kawabata, R. Wakatabe, M. Higuchi, H. Yamaya, H. Umehara, and I. Ishikawa Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System Blood, August 15, 2006; 108(4): 1381 - 1387. [Abstract] [Full Text] [PDF] D. D. Harrison-Findik, D. Schafer, E. Klein, N. A. Timchenko, H. Kulaksiz, D. Clemens, E. Fein, B. Andriopoulos, K. Pantopoulos, and J. Gollan Alcohol Metabolism-mediated Oxidative Stress Down-regulates Hepcidin Transcription and Leads to Increased Duodenal Iron Transporter Expression J. Biol. Chem., August 11, 2006; 281(32): 22974 - 22982. [Abstract] [Full Text] [PDF] D. Pospisilova, M. P. Mims, E. Nemeth, T. Ganz, and J. T. Prchal DMT1 mutation: response of anemia to darbepoetin administration and implications for iron homeostasis. Blood, July 1, 2006; 108(1): 404 - 405. [Full Text] [PDF] D. W. Swinkels, M. C.H. Janssen, J. Bergmans, and J. J.M. Marx Hereditary Hemochromatosis: Genetic Complexity and New Diagnostic Approaches Clin. Chem., June 1, 2006; 52(6): 950 - 968. [Abstract] [Full Text] [PDF] C. Peyssonnaux, A. S. Zinkernagel, V. Datta, X. Lauth, R. S. Johnson, and V. Nizet TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens Blood, May 1, 2006; 107(9): 3727 - 3732. [Abstract] [Full Text] [PDF] A Pietrangelo Molecular insights into the pathogenesis of hereditary haemochromatosis. Gut, April 1, 2006; 55(4): 564 - 568. [Full Text] [PDF] L. Viatte, G. Nicolas, D.-Q. Lou, M. Bennoun, J.-C. Lesbordes-Brion, F. Canonne-Hergaux, K. Schonig, H. Bujard, A. Kahn, N. C. Andrews, et al. Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice Blood, April 1, 2006; 107(7): 2952 - 2958. [Abstract] [Full Text] [PDF] T. Ganz and E. Nemeth Iron imports. IV. Hepcidin and regulation of body iron metabolism Am J Physiol Gastrointest Liver Physiol, February 1, 2006; 290(2): G199 - G203. [Abstract] [Full Text] [PDF] T. Ganz Hepcidin and Its Role in Regulating Systemic Iron Metabolism Hematology, January 1, 2006; 2006(1): 29 - 35. [Abstract] [Full Text] [PDF] C. Camaschella Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders Blood, December 1, 2005; 106(12): 3710 - 3717. [Abstract] [Full Text] [PDF] I. Kasvosve, Z. A. Gomo, K. J Nathoo, P. Matibe, B. Mudenge, M. Loyevsky, and V. R Gordeuk Effect of ferroportin Q248H polymorphism on iron status in African children Am. J. Clinical Nutrition, November 1, 2005; 82(5): 1102 - 1106. [Abstract] [Full Text] [PDF] E. Kemna, H. Tjalsma, C. Laarakkers, E. Nemeth, H. Willems, and D. Swinkels Novel urine hepcidin assay by mass spectrometry Blood, November 1, 2005; 106(9): 3268 - 3270. [Abstract] [Full Text] [PDF] P S Leung, S K Srai, M Mascarenhas, L J Churchill, and E S Debnam Increased duodenal iron uptake and transfer in a rat model of chronic hypoxia is accompanied by reduced hepcidin expression Gut, October 1, 2005; 54(10): 1391 - 1395. [Abstract] [Full Text] [PDF] H. Makui, R. J. Soares, W. Jiang, M. Constante, and M. M. Santos Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading Blood, September 15, 2005; 106(6): 2189 - 2195. [Abstract] [Full Text] [PDF] S. Rivera, E. Nemeth, V. Gabayan, M. A. Lopez, D. Farshidi, and T. Ganz Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs Blood, September 15, 2005; 106(6): 2196 - 2199. [Abstract] [Full Text] [PDF] S. A. B. Knight, G. Vilaire, E. Lesuisse, and A. Dancis Iron Acquisition from Transferrin by Candida albicans Depends on the Reductive Pathway Infect. Immun., September 1, 2005; 73(9): 5482 - 5492. [Abstract] [Full Text] [PDF] E. Kemna, P. Pickkers, E. Nemeth, H. van der Hoeven, and D. Swinkels Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS Blood, September 1, 2005; 106(5): 1864 - 1866. [Abstract] [Full Text] [PDF] L. Detivaud, E. Nemeth, K. Boudjema, B. Turlin, M.-B. Troadec, P. Leroyer, M. Ropert, S. Jacquelinet, B. Courselaud, T. Ganz, et al. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function Blood, July 15, 2005; 106(2): 746 - 748. [Abstract] [Full Text] [PDF] A. Maccio, C. Madeddu, D. Massa, M. C. Mudu, M. R. Lusso, G. Gramignano, R. Serpe, G. B. Melis, and G. Mantovani Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia Blood, July 1, 2005; 106(1): 362 - 367. [Abstract] [Full Text] [PDF] G. Papanikolaou, M. Tzilianos, J. I. Christakis, D. Bogdanos, K. Tsimirika, J. MacFarlane, Y. P. Goldberg, N. Sakellaropoulos, T. Ganz, and E. Nemeth Hepcidin in iron overload disorders Blood, May 15, 2005; 105(10): 4103 - 4105. [Abstract] [Full Text] [PDF] X. Lauth, J. J. Babon, J. A. Stannard, S. Singh, V. Nizet, J. M. Carlberg, V. E. Ostland, M. W. Pennington, R. S. Norton, and M. E. Westerman Bass Hepcidin Synthesis, Solution Structure, Antimicrobial Activities and Synergism, and in Vivo Hepatic Response to Bacterial Infections J. Biol. Chem., March 11, 2005; 280(10): 9272 - 9282. [Abstract] [Full Text] [PDF] S. Rivera, L. Liu, E. Nemeth, V. Gabayan, O. E. Sorensen, and T. Ganz Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia Blood, February 15, 2005; 105(4): 1797 - 1802. [Abstract] [Full Text] [PDF] E. Nemeth, A. Roetto, G. Garozzo, T. Ganz, and C. Camaschella Hepcidin is decreased in TFR2 hemochromatosis Blood, February 15, 2005; 105(4): 1803 - 1806. [Abstract] [Full Text] [PDF] P. Lee, H. Peng, T. Gelbart, L. Wang, and E. Beutler Regulation of hepcidin transcription by interleukin-1 and interleukin-6 PNAS, February 8, 2005; 102(6): 1906 - 1910. [Abstract] [Full Text] [PDF] R.J. MacIsaac, C. Tsalamandris, S. Panagiotopoulos, T.J. Smith, K.J. McNeill, G. Jerums, X Bai, D. Miao, J. Li, D. Goltzman, et al. Type 2 Diabetes: Absence of Proteinuria Does Not Preclude Loss of Renal Function: Nonalbuminuric Renal Insufficiency in Type 2 Diabetes. Diabetes Care 27: 195-200, 2004 J. Am. Soc. Nephrol., February 1, 2005; 16(2): 284 - 290. [Full Text] [PDF] M. D. Knutson, M. Oukka, L. M. Koss, F. Aydemir, and M. Wessling-Resnick Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin PNAS, February 1, 2005; 102(5): 1324 - 1328. [Abstract] [Full Text] [PDF] M J Brookes, N K Sharma, C Tselepis, and T H Iqbal Serum pro-hepcidin: measuring active hepcidin or a non-functional precursor? Gut, January 1, 2005; 54(1): 169 - 170. [Full Text] [PDF] H. Kawabata, R. E. Fleming, D. Gui, S. Y. Moon, T. Saitoh, J. O'Kelly, Y. Umehara, Y. Wano, J. W. Said, and H. P. Koeffler Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis Blood, January 1, 2005; 105(1): 376 - 381. [Abstract] [Full Text] [PDF] E. Nemeth, M. S. Tuttle, J. Powelson, M. B. Vaughn, A. Donovan, D. M. Ward, T. Ganz, and J. Kaplan Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization Science, December 17, 2004; 306(5704): 2090 - 2093. [Abstract] [Full Text] [PDF] J. Krijt, M. Vokurka, K.-T. Chang, and E. Necas Expression of Rgmc, the murine ortholog of hemojuvelin gene, is modulated by development and inflammation, but not by iron status or erythropoietin Blood, December 15, 2004; 104(13): 4308 - 4310. [Abstract] [Full Text] [PDF] H. McGrath Jr and P. G. Rigby Hepcidin: inflammation's iron curtain Rheumatology, November 1, 2004; 43(11): 1323 - 1325. [Full Text] [PDF] K J H Robson, A T Merryweather-Clarke, E Cadet, V Viprakasit, M G Zaahl, J J Pointon, D J Weatherall, and J Rochette Recent advances in understanding haemochromatosis: a transition state J. Med. Genet., October 1, 2004; 41(10): 721 - 730. [Abstract] [Full Text] [PDF] S. Yamaji, P. Sharp, B. Ramesh, and S. K. Srai Inhibition of iron transport across human intestinal epithelial cells by hepcidin Blood, October 1, 2004; 104(7): 2178 - 2180. [Abstract] [Full Text] [PDF] T. Matthes, P. Aguilar-Martinez, L. Pizzi-Bosman, R. Darbellay, L. Rubbia-Brandt, E. Giostra, M. Michel, T. Ganz, and P. Beris Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5'-UTR of the HAMP gene Blood, October 1, 2004; 104(7): 2181 - 2183. [Abstract] [Full Text] [PDF] J. CRAWLEY REDUCING THE BURDEN OF ANEMIA IN INFANTS AND YOUNG CHILDREN IN MALARIA-ENDEMIC COUNTRIES OF AFRICA: FROM EVIDENCE TO ACTION Am J Trop Med Hyg, August 1, 2004; 71(2_suppl): 25 - 34. [Abstract] [Full Text] [PDF] P. Lee, H. Peng, T. Gelbart, and E. Beutler The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and {beta}2-microglobulin-deficient hepatocytes PNAS, June 22, 2004; 101(25): 9263 - 9265. [Abstract] [Full Text] [PDF] A. Pietrangelo Hereditary Hemochromatosis -- A New Look at an Old Disease N. Engl. J. Med., June 3, 2004; 350(23): 2383 - 2397. [Full Text] [PDF] A. H. Laftah, B. Ramesh, R. J. Simpson, N. Solanky, S. Bahram, K. Schumann, E. S. Debnam, and S. K. S. Srai Effect of hepcidin on intestinal iron absorption in mice Blood, May 15, 2004; 103(10): 3940 - 3944. [Abstract] [Full Text] [PDF] K J Robson Hepcidin and its role in iron absorption Gut, May 1, 2004; 53(5): 617 - 619. [Abstract] [Full Text] [PDF] A P Walker, J Partridge, S K Srai, and J S Dooley Hepcidin: what every gastroenterologist should know Gut, May 1, 2004; 53(5): 624 - 627. [Full Text] This Article Abstract Full Text (PDF) All Versions of this Article: 2002-10-3235v1 101/7/2461    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nemeth, E. Articles by Ganz, T. Search for Related Content PubMed PubMed Citation Articles by Nemeth, E. Articles by Ganz, T. Related Collections Red Cells Plenary Papers Gene Expression Brief Reports Social Bookmarking                   What's this?

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020