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Cited by 498Iron Metabolism and DisordersErythropoietin and Anemia TreatmentFerroptosis and cancer prognosis

Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS

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Kemna, Erwin, Pickkers, Peter, Nemeth, Elizabeta, van der Hoeven, Hans, Swinkels, Dorine·2005·Blood
DOI 10.1182/blood-2005-03-1159
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Abstract

Hepatic peptide hormone hepcidin is the key regulator of iron metabolism and the mediator of anemia of inflammation. Previous studies indicated that interleukin-6 (IL-6) mediates hepcidin increase and consequent hypoferremia during inflammation. Here we used an in vivo human endotoxemia model to analyze the effects of lipopolysaccharide (LPS) as a more upstream inflammation activator. The temporal associations between plasma cytokines, hepcidin levels, and serum iron parameters were studied in 10 healthy individuals after LPS injection. IL-6 was dramatically induced within 3 hours after injection, and urinary hepcidin peaked within 6 hours, followed by a significant decrease in serum iron. Serum prohepcidin showed no significant change within a 22-hour time frame. These in vivo human results confirm the importance of the IL-6-hepcidin axis in the development of hypoferremia in inflammation and highlight the rapid responsiveness of this iron regulatory system. (Blood. 2005;106: 1864-1866)

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  • As a consequence, absorption of iron from the diet is reduced due to hepcidin mediated reduction of ferroportin expression in enterocytes, reducing circulating iron levels, further aggravated by inhibition of iron export from macrophages.

    “As a consequence of this interaction, the absorption of iron from the diet is reduced due to hepcidin mediated reduction of ferroportin expression in enterocytes, thereby resulting in a reduction of circulating iron levels which is further aggravated by the inhibition of iron export from macrophages by the same mechanism (Nemeth et al., 2004a; Kemna et al., 2005; Roy et al., 2007; Theurl et al., 2”

    From Iron at the interface of immunity and infection (2014) · cites this paper as Kemna et al., 2005

    The Results and discussion (page not provided) report that hepcidin rose before serum iron fell after LPS injection. They describe ferroportin internalization as a possible explanation and say blocking macrophage iron export would be expected to lower plasma iron. The paper does not address reduced dietary iron absorption or ferroportin expression in enterocytes, and it presents the macrophage mechanism as an explanation rather than a demonstrated cause in these subjects. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Hepcidin is overexpressed in inflammatory disease and is an early inflammatory marker.

    “However, hepcidin is overexpressed in inflammatory disease and is an early inflammatory marker [245,341-345].”

    From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [343]

  • Sustained elevation of hepcidin expression results in anemia due to reduced availability of iron for erythropoiesis.

    “Sustained elevation of hepcidin expression, as occurs in many inflammatory states, results in anemia due to reduced availability of iron for erythropoiesis, a condition previously known as “anemia of chronic disease” and more accurately renamed as “anemia of inflammation” [16,22,23].”

    From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [22]

  • Elevated hepcidin concentrations during inflammation and infections contribute to hypoferremia and, if chronic, to iron-restricted erythropoiesis and anemia.

    “Thus, elevated hepcidin concentrations during inflammation and infections contribute to hypoferremia [11,21] and, if chronic, to iron-restricted erythropoiesis and anemia [22].”

    From Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans (2015) · cites this paper as [21]

  • When IL-6 was detected, it was at considerably lower levels than in other conditions where hepcidin is notably induced; IL-6 was typically one or more orders of magnitude higher during uncomplicated malaria, sepsis, or experimental endotoxemia.

    “When IL-6 was detected, it was at considerably lower levels than in other conditions where hepcidin is notably induced: IL-6 was typically one or more orders of magnitude higher during uncomplicated malaria [24], sepsis [45], or experimental endotoxemia [21].”

    From Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans (2015) · cites this paper as [21]

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Cites

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Research works printed but not linked: 9

  1. Weinstein DA, Roy CN, Fleming MD, et al. Inap- propriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;100: 3776-3781.
  2. Nicolas G, Bennoun M, Porteu A, et al. Severe iron deficiency anemia in transgenic mice ex- pressing liver hepcidin. Proc Natl Acad Sci U S A. 2002;99:4596-4601.
  3. Roetto A, Papanikolaou G, Politou M, et al. Mu- tant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33:21-22.
  4. 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.
  5. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2003;101: 2461-2463.
  6. Prabhakar U, Eirikis E, Davis HM. Simultaneous quantification of proinflammatory cytokines in hu- man plasma using the LabMAP assay. J Immunol Methods. 2002;260:207-218.
  7. Ashrafian H. Hepcidin: the missing link between hemochromatosis and infections. Infect Immun. 2003;71:6693-6700.
  8. Johnson KJ, Chensue SW, Ward PA. Immunopa- thology. In: Rubin E, Farber JL, eds. Pathology. Philadelphia, PA: JB Lippincott; 1999:105-152.
  9. Kulaksiz H, Gehrke SG, Janetzko A, et al. Pro- hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemo- chromatosis, chronic renal insufficiency, and re- nal anaemia. Gut. 2004;53:735-743.

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Authors
Kemna, E., Pickkers, P., Nemeth, E., van der Hoeven, H., & Swinkels, D.
Affiliations
  • Radboud University Nijmegen (NL)
  • From the Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, The Netherlands; Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, The Netherlands; and Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2005-09-01
Volume
106
Issue
5
Pages
1864-1866
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2005-03-1159
OpenAlex
W2061035099
Cited by
498
References
7
Citations by year
2026: 6 · 2025: 7 · 2024: 4 · 2023: 10 · 2022: 17 · 2021: 8 · 2020: 19 · 2019: 20 · 2018: 21 · 2017: 20 · 2016: 30 · 2015: 31 · 2014: 27 · 2013: 38 · 2012: 36
FWCI
15.95
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords
hepcidin, lipopolysaccharide, endotoxemia, interleukin-6, serum iron, hypoferremia, anemia of chronic disease, iron metabolism, prohepcidin, plasma cytokines, inflammation
MeSH terms
Adolescent, Adult, C-Reactive Protein, Female, Humans, Injections, Intravenous, Iron, Lipopolysaccharides, Male, Reference Values, Time Factors, Interleukin-6, Cytokines, Endotoxemia, Antimicrobial Cationic Peptides, Hepcidins

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