The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index; 11 of the 30 sources its claims cite were checked for support.
IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin
Open accessAbstract
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. Methods Macrophage culture.Monocytes from peripheral blood were isolated by centrifugation through Ficoll-Paque (Amersham Pharmacia Biotech, Piscataway, New Jersey, USA) and 46% iso-Nonstandard abbreviations used: anemia of inflammation (AI); Iscove's modified Dulbecco's medium (IMDM); medium from LPS-stimulated macrophages (M-LPS); medium from unstimulated macrophages (M); recombinant human IL-6 (rhIL-6); total iron-binding capacity (TIBC); unsaturated iron-binding capacity (UIBC). Conflict of interest:The authors have declared that no conflict of interest exists.
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Claims the paper makes
11 of 30 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“patients with AI due to inflammatory disorders or infections had markedly increased excretion of urinary hepcidin”
What the sources say
- Supportedcites [12] source
The Results and discussion report elevated urinary hepcidin excretion in patients diagnosed with anemia of inflammation compared with healthy subjects and other patient groups. The same section reports very high excretion in a patient with epididymitis and sepsis, supporting the infection component of the claim. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“decreased serum iron”
What the sources say
- Supportedcites [8] Nicolas, 2002, J. Clin. Invest. source
The Results section reports a twofold decrease in serum iron in wild-type mice 16 hours after turpentine injection (Figure 6a). It also notes that this decrease was not observed in hepcidin-deficient mice. (LLM, conf=0.95)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“injections of turpentine increased hepcidin mRNA”
What the sources say
- Supportedcites [8] Nicolas, 2002, J. Clin. Invest. source
The Results section reports a sixfold increase in liver hepcidin gene expression 16 hours after turpentine injection compared with saline-injected controls. The discussion (p. 1042) explicitly describes this as a sixfold increase in liver hepcidin mRNA in mice. (LLM, conf=0.95)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“strong induction of hepcidin mRNA by IL-6”
What the sources say
- Supportedcites [12] source
The Results and discussion section reports that IL-6 induced hepcidin in primary human hepatocytes within 8 hours, with a 25-fold increase. The Figure 2 caption identifies the measured signal as hepcidin mRNA. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“but not IL-1 α or TNFα”
What the sources say
- Supportedcites [12] source
The Results and discussion section reports that IL-1α and TNF-α did not induce hepcidin mRNA within eight hours in primary human hepatocytes, unlike IL-6. It also notes that IL-1α induced hepcidin mRNA after 24 hours, probably indirectly through IL-6; the claim is consistent with the lack of strong direct induction. (LLM, conf=0.90)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LPS treatment increased hepcidin mRNA levels in primary human hepatocytes”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Anti-TNFα Ab's had no detectable effect in either experiment”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hep3B hepcidin mRNA, however, markedly increased after exposure to M-LPS”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Anti-IL-6 Ab's had similar inhibitory effects when hepatocytes or Hep3B cells were treated with conditioned medium from macrophages exposed to peptidoglycan from Staphylococcus aureus”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“in IL-6 KO mice hepcidin mRNA increased ninefold”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 10
- It may state two separate claims as one. 17
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“hepcidin synthesis is regulated by dietary iron and iron stores, as well as by tissue oxygenation”
What the sources say
- Not checked — no full text of the sourcecites [3] source
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
Section 3.4 reports increased liver HEPC1 and HEPC2 transcripts in mice given dietary carbonyl iron or injected iron–dextran, supporting regulation by iron excess. The paper does not establish regulation by iron stores specifically, and no passage addresses tissue oxygenation; it measures gene expression rather than hepcidin synthesis directly. (LLM, conf=0.88)
- Partly supportedcites [8] Nicolas, 2002, J. Clin. Invest. sourceExperimental — accuracy not yet measured
The hypoxia results report that reduced tissue oxygenation downregulated hepcidin gene expression in mice. The anemia results show that iron loading increased expression, and the Discussion links iron deficiency to low expression until stores are repleted. The paper does not show that dietary iron itself regulates hepcidin synthesis; it describes hepcidin regulating dietary iron absorption instead. (LLM, conf=0.87)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the turpentine-induced hypoferremia was not observed in hepcidin-deficient mice (8), demonstrating that hepcidin is required for iron sequestration during inflammatory conditions”
What the sources say
- Partly supportedcites [8] Nicolas, 2002, J. Clin. Invest. sourceExperimental — accuracy not yet measured
The results and discussion (p. 1042) report that turpentine lowered serum iron in wild-type mice but not in hepcidin-deficient mice. They establish hepcidin’s role in the inflammatory fall in serum iron, but describe iron sequestration as a proposed mechanism, not one directly demonstrated by that experiment. (LLM, conf=0.84)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“hepcidin mRNA expression was increased in mice with dietinduced or genetically induced iron overload”
What the sources say
- Not checked — no full text of the sourcecites [3] source
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
Section 3.4 reports increased liver HEPC1 and HEPC2 transcripts in mice given dietary carbonyl iron, supporting the diet-induced part. The paper does not report increased hepcidin mRNA in genetically iron-overloaded mice; its Introduction instead describes iron overload in USF2 knockout mice that lack hepcidin transcripts. Page numbers are not available in our copy. (LLM, conf=0.87)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
Every source the paper cites for this claim was checked and supports it.
In the paper
“decreased in mice with anemia caused by bleeding or hemolysis or in mice with hypoxemia due to decreased ambient oxygen”
What the sources say
- Supportedcites [8] Nicolas, 2002, J. Clin. Invest. source
In “Hepcidin gene expression is decreased after experimentally induced anemia,” the paper reports reduced liver hepcidin mRNA after bleeding and reduced hepcidin expression after PHZ-induced hemolytic anemia. In “Hepcidin gene expression is tightly controlled by hypoxia,” it reports downregulation in mice exposed to reduced oxygen pressure in a hypobaric chamber. The hypoxic reduction was clear after two and four days, though results varied after twelve days. (LLM, conf=0.93)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“in the most common form of hemochromatosis, that caused by mutations in the HFE gene”
What the sources say
- Not checked — no full text of the sourcecites [11] source
- Could not verifycites [12] sourceExperimental — accuracy not yet measured
The Results and discussion (page unavailable) compare urinary hepcidin in patients with well-controlled hereditary hemochromatosis with levels in patients with anemia of inflammation, but do not say hepcidin production is diminished relative to healthy people. A search for HFE mutations found no passage identifying the hemochromatosis patients as having HFE-related disease. (LLM, conf=0.76)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IL-6 infusion rapidly increased hepcidin excretion (Figure 4B); within 2 hours after the infusion, urinary hepcidin levels were 7.5-fold higher on average than at 0 hours”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“serum iron decreased on average 34% and transferrin saturation decreased 33% in comparison to preinfusion values”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TNFα markedly suppressed hepcidin mRNA levels by a mechanism that did not involve IL-6 regulation”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“both the effects of LPS on primary human hepatocytes and the effects of M-LPS on Hep3B cells were completely reversed when IL-6-neutralizing Ab's were added”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“median haptoglobin mRNA was 9.3-fold higher in turpentine-treated WT mice but only 1.9-fold higher in IL-6 KO mice”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The inflammatory and iron pathways of hepcidin stimulation respond rapidly, with major hepcidin increase detectable within 1 day in both humans and mice”
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“hepcidin mRNA was increased in the livers of LPS-treated mice and in LPS-treated hepatocytes”
What the sources say
- Not checked — no full text of the sourcecites [3] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“There is a single human hepcidin gene whose essential role in iron homeostasis was confirmed by identifying homozygous frameshift or nonsense mutations in affected individuals with severe juvenile hemochromatosis”
What the sources say
- Not checked — no full text of the sourcecites [9] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“in transgenic mice overexpressing hepcidin-1 (4), transplacental and intestinal iron transport was blocked, and the mice died at birth from severe iron deficiency unless given parenteral iron supplementation”
What the sources say
- Not checked — no full text of the sourcecites [4] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations suggest that human hepcidin is the functional equivalent of hepcidin-1 in mice.”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Overexpression of the other known murine hepcidin gene, hepcidin-2, had no effect on iron metabolism in mice”
What the sources say
- Not checked — no full text of the sourcecites [6] source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Hepcidin production was also diminished in another form of juvenile hemochromatosis due to mutations in the hemojuvelin gene”
What the sources say
- Not checked — no full text of the sourcecites [10] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Hepatic hepcidin mRNA levels in mice were shown to increase in response to increased dietary iron”
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In IL-6 KO mice, however, hepcidin mRNA was suppressed, likely due to the negative regulation of hepcidin synthesis by other acute-phase cytokines”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“changes in serum iron concentrations reflected the pattern of hepcidin induction: turpentine treatment caused serum iron decrease in WT mice, but no change in iron levels was detected in IL-6 KO mice”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the decrease in iron supply becomes a bottleneck for hemoglobin synthesis and eventually results in anemia”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When the rate of iron release from macrophages drops, plasma iron concentrations rapidly decrease”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“there are at least three major and distinct pathways of regulation of hepcidin: regulation by inflammation, dependent on IL-6; regulation by iron, dependent on some other factor, perhaps transferrin saturation; and suppression of hepcidin production during hypoxia and anemia”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“transgenic overexpression of IL-6 in mice (36) and repeated administration of IL-6 in rats and cancer patients (33) has been reported to cause anemia”
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
IL-6 KO mice do not produce functional IL-6.
“Two pairs of IL-6 -/- (IL-6 KO) mice on a C57BL/6 background”
The paper relies on this without support.
Hepatic hepcidin mRNA levels reflect hepcidin synthesis or activity.
“Median hepcidin-1 expression in the liver increased 12-fold”
The paper relies on this without support.
Turpentine-induced inflammation in mice is a valid model of human inflammatory hypoferremia.
“we used the turpentine-induced mouse model of inflammation”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“increased concentrations of hepcidin then inhibit ferroportin activity”
From Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“leading to depletion of iron in plasma and extracellular fluid (hypoferremia).”
From Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis (2021) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 Nemeth et al., 2004a
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Infection and inflammation induce hepcidin, predominantly through the effects of the cytokine interleukin-6 (IL-6) [52]”
From Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis (2021) · cites this paper as [52]
The cited source says what the claim attributes to it.
In the citing paper
“Blockade of IL-6 receptor signaling prevented the hepatocyte-derived generation of hepcidin, which interferes with iron absorption (Nemeth et al., 2004”
From Targeting Interleukin-6 Signaling in Clinic (2019) · cites this paper as Nemeth et al., 2004
In the citing paper
“Interleukin-6 (IL-6) is the main cytokine that stimulates hepcidin synthesis during infection19 and inflammation, but other factors can also contribute, including activin B20, type I interferons (IFNs)21,22 and BMP2 (REF. 23).”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [19]
In the citing paper
“Proinflammatory cytokines induced by inflammation can stimulate anemia of inflammation by limiting serum iron and increasing cellular iron stores by modulating the expression and activity of various iron regulatory proteins including hepcidin, FPN, ferritin, and the iron importer divalent metal transporter 1 (DMT1) [25–30].”
From The utility of iron chelators in the management of inflammatory disorders (2015) · cites this paper as [25]
In the citing paper
“However, hepcidin is overexpressed in inflammatory disease and is an early inflammatory marker [245,341-345].”
In the citing paper
“during an inflammatory episode interleukin-6 (IL-6) signals to the liver to release the hormone hepcidin, which promotes iron accumulation in phagocytic cells by inducing degradation of the iron exporter ferroportin (Fpn1) (Nemeth et al., 2004).”
From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Nemeth et al., 2004
In the citing paper
“The inflammatory increase in hepcidin is mainly caused by increased concentrations of IL-6 (interleukin-6) [19], inducing the transcription of the hepcidin gene through the JAK2/STAT3 [20][21][22] pathway.”
From Iron and infection (2018) · cites this paper as [19]
In the citing paper
“The role of IL-6 is important in many models of infection and inflammation [19,24] but in some models other cytokines may partially replace its stimulatory effect on hepcidin [17].”
From Iron and infection (2018) · cites this paper as [19]
In the citing paper
“One main contributing factor to pathologic iron homeostasis is interleukin (IL)-6 mediated induction of hepcidin expression through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway [154].”
From Iron in immune cell function and host defense (2021) · cites this paper as [154]
In the citing paper
“During inflammation, HAMP is induced in hepatocytes alongside a battery of other acute‐phase proteins, downstream of interleukin‐6 and toll‐like receptor signalling‐associated pathways. 98”
From The battle for iron in enteric infections (2020) · cites this paper as [98]
In the citing paper
“To correct this, all animals were conditioned on a low-iron diet (2-4 ppm iron; Teklad diet TD.80396, Envigo) for 5-7 days prior to, and throughout the duration of, all experiments.”
From Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia (2017) · cites this paper as [43]
In the citing paper
“Accordingly, IL6 is a key mediator of inflammation-driven iron handling, as it induces the production of hepcidin, the master regulator of iron homeostasis [4].”
In the citing paper
“It has been suggested that the COVID-19 related inflammation may be the main cause of COVID-19 associated iron disorders, as an inflammation-driven dysregulation of iron homeostasis is well established [4, 6, 7].”
In the citing paper
“The study of hepcidin regulation in mice housed under standard conditions is confounded by the high iron content of most commercial mouse chow blends.”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [16]
In the citing paper
“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 [16]
In the citing paper
“In animal models, diverse inflammatory and infectious stimuli, including Streptococcus species, Pseudomonas aeruginosa, Aspergillus fumigatus, influenza, turpentine, and lipopolysaccharide (LPS) robustly induce hepcidin in the liver via the induction of IL-6, resulting in rapid reduction in serum iron levels [16,19–21].”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [16]
In the citing paper
“In the context of inflammation, IL-6 and IL-22 stimulate HAMP expression via specific receptors signaling through signal transducer and activator of transcription (STAT)-3, while alpha-1 antitrypsin may do so via HJV and matriptase-2 [69–71].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [70]
In the citing paper
“but is also an acute phase protein upregulated by inflammatory cytokines, notably IL-6 [18–20].”
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 [19]
In the citing paper
“During neuroinflammation, glial cells are activated, which perturbs iron homoeostasis.34,35”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [35]
In the citing paper
“Serum sTR concentration reflects total erythroid activity and iron status and has been shown to reflect plasma iron turnover and erythroid transferrin uptake if iron deficiency is not present (22,25).”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [22]
In the citing paper
“Serum sTR concentration reflects total erythroid activity in rats and humans and has been shown to reflect plasma iron turnover and erythroid transferrin uptake very closely if iron deficiency is not present (22).”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [22]
In the citing paper
“We found that the hepatocytelike cells of the adenomas expressed very high levels of hepcidin 100 and speculated that our results could be generalized-that induction of hepcidin expression in response to inflammation might explain the anemia of chronic disease.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [197]
In the citing paper
“In mice, HFE2 is localized to the surface of periportal hepatocytes, and HFE2-mutant mice display iron loading and a striking decrease in hepcidin upregulation in response to increased iron from exogenous sources, compared with controls (217).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [217]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Human iron-supplementation participant count differs
MinorThe Methods section says six volunteers participated in the iron-supplementation study, while the Results section says five subjects took the iron supplements.
“Six healthy volunteers collected first morning urine for 9 days.”
“Five subjects took 65 mg of iron (as ferrous sulfate) for 3 days, and their urinary hepcidin was monitored before, during, and after iron supplementation.”
Citations
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Hepcidin, a urinary antimicrobial peptide synthesized in the liver
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Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation
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Self-citationHepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein
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Self-citationLEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity
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Age-Associated Increased Interleukin-6 Gene Expression, Late-Life Diseases, and Frailty
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Healy, C. M., Muñoz‐Wolf, N., Strydom, J., Faherty, L., Williams, N. C., Kenny, S., Donnelly, S. C., & Cloonan, S. M. (2021) · Respiratory Research · doi:10.1186/s12931-021-01722-y · Cited by 90
Kassa, E., Enawgaw, B., Gelaw, A., & Gelaw, B. (2016) · BMC Hematology · doi:10.1186/s12878-015-0037-1 · Cited by 89
“[23] explain the mechanism behind the occurrence of anemia in pulmonary tuberculosis patients saying that the invasion of bacteria leads to activation of T-lymphocyte and macrophages, which induce the production of the cytokines like interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), Interlukin-1 (IL-1) an…”
BackgroundHepcidin and iron disorders: new biology and clinical approaches
Arezes, J., & Nemeth, E. (2015) · International Journal of Laboratory Hematology · doi:10.1111/ijlh.12358 · Cited by 88
“Multiple cytokines are known to increase hepcidin production, including IL-6, IL-22, activin B, and BMP2.”
BackgroundInfluentialSelf-citationGillen, K. M., Mubarak, M., Nguyen, T. D., & Pitt, D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00255 · Cited by 88
“In activated macrophages, accumulation of iron is promoted by IL-6 and IL-1β, which induce the iron regulatory hormone hepcidin (69, 72, 73).”
BackgroundAnemia of Chronic Disease and Iron Deficiency Anemia in Inflammatory Bowel Diseases
Murawska, N., Fabisiak, A., & Fichna, J. (2016) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000648 · Cited by 93
“Inflammation-dependent signals regulating hepcidin involve IL-6 and Bone Morphogenetic Protein (BMP) receptor.(88,89) In addition, a recent study by Wallace and Subramanian(90) showed IL-22 to induce hypoferremic state and hepcidin FIGURE 2.”
BackgroundXin, H., Wang, M., Tang, W., Shen, Z., Miao, L., Wu, W., Li, C., Wang, X., Xin, X., & Zhu, Y. Z. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6315 · Cited by 87
“Lipopolysaccharide (LPS) is widely used to induce hepatic hepcidin and inflammatory anemia in experimental conditions (16, 29, 39, 45).”
Crohnʼs disease is associated with restless legs syndrome
Weinstock, L. B., Bosworth, B. P., Scherl, E., Li, E., Iroku, U., Munsell, M. A., Mullen, G. E., & Walters, A. S. (2009) · Inflammatory Bowel Diseases · doi:10.1002/ibd.20992 · Cited by 87
“Proinflammatory cytokines, such as interleukin-6 (IL-6), have been shown to increase production of a small peptide, hepcidin, which affects iron transport in in vitro models and in healthy human volunteers.(30) We hypothesize that inflammation attributable to other systemic(13,31) and GI-related disorders, such as CD,…”
BackgroundTargeting the Hepcidin-Ferroportin Axis in the Diagnosis and Treatment of Anemias
Nemeth, E. (2009) · Advances in Hematology · doi:10.1155/2010/750643 · Cited by 88
“Of inflammatory mediators regulating hepcidin, IL-6 was shown to be a prominent inducer in vitro and in vivo, and it stimulates hepcidin transcription through a STAT-3 dependent mechanism [38, 39].”
Self-citationMillot, S., Andrieu, V., Lettéron, P., Lyoumi, S., Hurtado-Nédelec, M., Karim, Z., Thibaudeau, O., Bennada, S., Charrier, J.-L., Lasocki, S., et al. (2010) · Blood · doi:10.1182/blood-2010-04-281840 · Cited by 95
Panichi, V., Scatena, A., Rosati, A., Giusti, R., Ferro, G., Malagnino, E., Capitanini, A., Piluso, A., Conti, P., Bernabini, G., et al. (2014) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfu345 · Cited by 87
“Thus, HEP represents a common effector of the homeostatic regulation of the intracellular iron fluxes in response to iron stores, erythroid and inflammatory regulators such as cytokines [9, 10, 40].”
BackgroundSystemic effects of IL-6 blockade in rheumatoid arthritis beyond the joints
Jarlborg, M., & Gabay, C. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155742 · Cited by 90
Wang, P., Song, S., Guo, H., Wang, T., Liu, N., & Yan, C. (2019) · Journal of Cancer · doi:10.7150/jca.31598 · Cited by 86
“Hepcidin, a regulator of iron metabolism, is increasingly expressed when plasma IL-6 level is elevated [83,84], which results in iron deficiency and anemia [80].”
BackgroundRegulation of systemic iron homeostasis: how the body responds to changes in iron demand
Anderson, G. J., Darshan, D., Wilkins, S. J., & Frazer, D. M. (2007) · BioMetals · doi:10.1007/s10534-006-9030-2 · Cited by 87
Disorders of Iron Metabolism and Anemia in Chronic Kidney Disease
Panwar, B., & Gutiérrez, O. M. (2016) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2016.05.002 · Cited by 87
“Interleukin-6, acting through the JAK2/STAT3 (JAK, Janus kinase; STAT, Signal Transducer and Activator of Transcription) pathway, interferon γ, and interleukin-1 appear to be the primary inflammatory inducers of hepcidin expression.(46,47) Other studies have shown that activin B uses the SMAD phosphorylation pathway t…”
BackgroundInflammation induces stress erythropoiesis through heme-dependent activation of SPI-C
Bennett, L. F., Liao, C., Quickel, M. D., Yeoh, B. S., Vijay–Kumar, M., Hankey‐Giblin, P., Prabhu, K. S., & Paulson, R. F. (2019) · Science Signaling · doi:10.1126/scisignal.aap7336 · Cited by 89
Heart failure and anemia: mechanisms and pathophysiology
Anand, I. S. (2008) · Heart Failure Reviews · doi:10.1007/s10741-008-9088-8 · Cited by 87
“Furthermore, IL-6 downregulates the expression of ferroportin, preventing the release of iron from body stores [48].”
BackgroundDitmer, M., Gabryelska, A., Turkiewicz, S., Białasiewicz, P., Małecka-Wojciesko, E., & Sochal, M. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm11010067 · Cited by 86
Sanad, M., Osman, M., & Gharib, A. (2011) · Italian Journal of Pediatrics · doi:10.1186/1824-7288-37-34 · Cited by 85
Interleukin-6 directly impairs the erythroid development of human TF-1 erythroleukemic cells
McCranor, B. J., Kim, M. J., Cruz, N. M., Xue, Q., Berger, A. E., Walston, J. D., Civin, C. I., & Roy, C. N. (2013) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2013.09.004 · Cited by 86
A Novel Immunological Assay for Hepcidin Quantification in Human Serum
Koliaraki, V., Marinou, M., Vassilakopoulos, T. P., Vavourakis, E., Tsochatzis, E. A., Pangalis, G. A., Papatheodoridis, G., Stamoulakatou, A., Swinkels, D. W., Papanikolaou, G. V., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004581 · Cited by 86
“Since interleukin-6 directly induces hepcidin expression, high hepcidin levels were expected, as we found in these patients [15,29,30].”
BackgroundMethodInfluentialAdaptive Evolution of Hepcidin Genes in Antarctic Notothenioid Fishes
Xu, Q., CHENG, C.-H. C., Hu, P., Ye, H., Chen, Z., Cao, L., Chen, L., Shen, Y., & Chen, L. (2008) · Molecular Biology and Evolution · doi:10.1093/molbev/msn056 · Cited by 85
“The NJ tree also showed taxonomic-specific expansions of hepcidin variants, indicating that duplication and diversification of hepcidin genes play important roles in evolutionary response to diverse ecological conditions.”
BackgroundRegulators of hepcidin expression
Roth, M., Meynard, D., & Coppin, H. (2019) · Vitamins and hormones · doi:10.1016/bs.vh.2019.01.005 · Cited by 86
Zimmermann, M. B., Troesch, B., Biebinger, R., Egli, I. M., Zeder, C., & Hurrell, R. F. (2009) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2009.28129 · Cited by 84
“In humans, oral iron challenge produces variable hepcidin responses in urine (18) and serum (14), but the interpretation of these studies is limited because the absorption of the iron doses was uncertain.”
BackgroundFan, Y., Liu, B., Chen, F., Song, Z., Han, B., Meng, Y., Hou, J., Cao, P., Chang, Y., & Tan, K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.612144 · Cited by 84
“A previous study reported that the induction of hepcidin can be triggered by IL-6, which plays an important role in the regulation of inflammation and the immune response (20).”
BackgroundInfluentialIs ferroportin–hepcidin signaling altered in restless legs syndrome?
Clardy, S. L., Wang, X., Boyer, P. J., Earley, C. J., Allen, R. P., & Connor, J. R. (2006) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2006.04.008 · Cited by 84
“When iron levels in the body are elevated, hepcidin complexes with FP on duodenal epithelial cells and is internalized and degraded, resulting in decreased cellular iron export [18,22,24].”
BackgroundPalliative Management of Fatigue at the Close of Life
Yennurajalingam, S., & Bruera, E. D. (2007) · JAMA · doi:10.1001/jama.297.3.295 · Cited by 84
“Anemia of chronic disease may be a result of elevated inflammatory cytokines.(61) In patients such as Mrs D who have a history of chronic anemia requiring blood transfusion, gastrointestinal malignancy may be a cause.”
BackgroundAltered Iron Metabolism Is Part of the Choroid Plexus Response to Peripheral Inflammation
Marques, F., Falcão, A. M., Sousa, J. C., Coppola, G., Geschwind, D. H., Sousa, N., Correia‐Neves, M., & Palha, J. A. (2009) · Endocrinology · doi:10.1210/en.2008-1610 · Cited by 86
Pattern of resistance to erythropoietin-stimulating agents in chronic kidney disease
Bamgbola, O. F. (2011) · Kidney International · doi:10.1038/ki.2011.179 · Cited by 84
“Iron is transported in the plasma by the transferrin carrier protein, which enhances its cellular uptake by binding to its surface receptors.(38) Cytokines may also upregulate iron cellular uptake by activating divalent metal transporter and/or transferrin.”
BackgroundFisiologia e metabolismo do ferro
Grotto, H. Z. W. (2010) · Revista Brasileira de Hematologia e Hemoterapia · doi:10.1590/s1516-84842010005000050 · Cited by 84
Cherian, S., Forbes, D., Cook, A. G., Sanfilippo, F. M., Kemna, E., Swinkels, D. W., & Burgner, D. P. (2008) · PLoS ONE · doi:10.1371/journal.pone.0004030 · Cited by 86
“Inter-relationship between hepcidin, IDA and H. pylori infection Hepcidin expression is induced by iron stores, and inflammation (particularly IL-6) [6,24,28].”
BackgroundInfluentialWeekly Iron as a Safe Alternative to Daily Supplementation for Nonanemic Pregnant Women
Casanueva, E., Viteri, F. E., Mares-Galindo, M., Meza-Camacho, C., Lorı́a, A., Schnaas, L., & Valdés‐Ramos, R. (2006) · Archives of Medical Research · doi:10.1016/j.arcmed.2005.11.011 · Cited by 83
Could Alzheimer’s Disease Originate in the Periphery and If So How So?
Morris, G., Berk, M., Maes, M. H. J., & Puri, B. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1092-y · Cited by 86
Lasocki, S., Millot, S., Andrieu, V., Lettéron, P., Pilard, N., Muzeau, F., Thibaudeau, O., Montravers, P., & Beaumont, C. (2008) · Critical Care Medicine · doi:10.1097/ccm.0b013e31818103b9 · Cited by 84
“IL-6 infusion in human healthy volunteers rapidly increases hepcidin urinary excretion with a concomitant drop in serum iron (28).”
BackgroundRenal Anemia of Inflammation: The Name Is Self-Explanatory
Yılmaz, M. İ., Solak, Y., Covic, A. C., Goldsmith, D. J. A., & Kanbay, M. (2011) · Blood Purification · doi:10.1159/000328037 · Cited by 83
“Especially IL-6 is the major driving force of hepcidin production under inflammatory conditions [”
BackgroundSow, F. B., Alvarez, G. R., Gross, R. P., Satoskar, A. R., Schlesinger, L. S., Zwilling, B. S., & Lafuse, W. P. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.1208719 · Cited by 83
“However, when IFN- was added together with IFN- and LPS, there was a statistically significant increase in hepcidin mRNA expression compared with cells stimulated with IFN- and LPS. IFN- also increased hepcidin mRNA expression in cells stimulated with IFN- Pam3CSK4, but the increase did not reach statistical significa…”
BackgroundInfluentialHepcidin is a key mediator of anemia of inflammation in Crohn's disease
Basseri, R. J., Nemeth, E., Vassilaki, M. E., Basseri, B., Enayati, P. J., Shaye, O. A., Bourikas, L. A., Ganz, T., & Papadakis, K. A. (2012) · Journal of Crohn s and Colitis · doi:10.1016/j.crohns.2012.10.013 · Cited by 85
Self-citationUnderstanding anemia of chronic disease
Fraenkel, P. G. (2015) · Hematology · doi:10.1182/asheducation-2015.1.14 · Cited by 88
Masson, C. (2011) · Joint Bone Spine · doi:10.1016/j.jbspin.2010.05.017 · Cited by 82
Interleukin-6: From identification of the cytokine to development of targeted treatments
Assier, É., Boissier, M., & Dayer, J. (2010) · Joint Bone Spine · doi:10.1016/j.jbspin.2010.07.007 · Cited by 88
van der Putten, K., Jie, K. E., van den Broek, D. A., Kraaijenhagen, R. J., Laarakkers, C. M., Swinkels, D. W., Braam, B. G., & Gaillard, S. (2010) · European Journal of Heart Failure · doi:10.1093/eurjhf/hfq099 · Cited by 82
“Hepcidin inhibits the efflux of iron into plasma transferrin by downregulating ferroportin, the efflux channel for iron in macrophages and in enterocytes.(6) Enhanced synthesis of hepcidin thus leads to inhibition of iron absorption in the small intestine and sequestering of iron in macrophages, resulting in limited i…”
BackgroundHanson, A., Mulè, M. P., Ruffieux, H., Mescia, F., Bergamaschi, L., Pelly, V. S., Turner, L., Kotagiri, P., Göttgens, B., Hess, C., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01754-8 · Cited by 83
Anaemia and iron deficiency in children with inflammatory bowel disease
Wiskin, A. E., Fleming, B. J., Wootton, S. A., & Beattie, R. M. (2012) · Journal of Crohn s and Colitis · doi:10.1016/j.crohns.2011.12.001 · Cited by 82
Anemia in Chronic obstructive pulmonary disease: Prevalence, pathogenesis, and potential impact
Sarkar, M. S., Rajta, P., & Khatana, J. (2015) · Lung India · doi:10.4103/0970-2113.152626 · Cited by 84
“It has been seen that IL‐6 knockout mice fail to produce hepcidin in response to inflammatory challenges, unlike that which normally occurs in wild‐type mice.[36] Regarding the role of IL‐1, there is a controversy.”
Iron regulator hepcidin impairs macrophage-dependent cardiac repair after injury
Zlatanova, I., Pinto, C., Bonnin, P., Mathieu, J. R. R., Bakker, W., Vilar, J., Lemitre, M., Voehringer, D., Vaulont, S., Peyssonnaux, C., et al. (2019) · Circulation · doi:10.1161/circulationaha.118.034545 · Cited by 81
Diurnal Rhythm rather than Dietary Iron Mediates Daily Hepcidin Variations
Schaap, C., Hendriks, J. C., Kortman, G. A. M., Klaver, S. M., Kroot, J. J., Laarakkers, C. M., Wiegerinck, E. T. G., Tjalsma, H., Janssen, M. C. H., & Swinkels, D. W. (2012) · Clinical Chemistry · doi:10.1373/clinchem.2012.194977 · Cited by 81
Zarruk, J. G., Berard, J. L., dos Santos, R. P., Kroner, A., Lee, J., Arosio, P., & David, S. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.02.001 · Cited by 79
“…Fpn. Fpn levels on the cell surface can be regulated by hepcidin, a 25 amino acid peptide, that binds to Fpn on the cell surface and induces its internalization and degradation by ubiquitination, ultimately resulting in reduced iron efflux and iron accumulation (Nemeth et al., 2004a,b).”
BackgroundRegulation of Hepcidin by Erythropoiesis: The Story So Far
Pasricha, S., McHugh, K., & Drakesmith, H. (2016) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071715-050731 · Cited by 84
“Hepcidin is also upregulated directly by systemic inflammation, chiefly by IL6 (54) but also by IL22 (5, 85), via the STAT3 pathway.”
BackgroundMuehlenbachs, A., Fried, M., Lachowitzer, J., Mutabingwa, T. K., & Duffy, P. E. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.1.557 · Cited by 81
“Hepcidin is a cytokine-induced peptide that is a key mediator of the anemia of inflammation (54).”
BackgroundKell, D. B., & Pretorius, E. (2014) · Integrative Biology · doi:10.1039/c4ib00173g · Cited by 81
Hepcidin expression and iron parameters change in Type 2 diabetic patients
Jiang, F., Sun, Z., Tang, Y., Xu, C., & Jiao, X. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.03.028 · Cited by 80
“tions, excessive cytokines produced by macrophages and Tlymphocytes, particularly IL-6 play a central role in the hepcidin production [19].”
BackgroundPharmacokinetics of Anti-hepcidin Monoclonal Antibody Ab 12B9m and Hepcidin in Cynomolgus Monkeys
Xiao, J. J., Krzyżański, W., Wang, Y., Li, H., Rose, M. J., Ma, M., Wu, Y., Hinkle, B., & Ruixo, J. J. P. (2010) · The AAPS Journal · doi:10.1208/s12248-010-9222-0 · Cited by 80
New insights into the regulation of iron homeostasis
Deicher, R., & Hörl, W. H. (2006) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2006.01633.x · Cited by 80
The role of adipocytes in the modulation of iron metabolism in obesity
Coimbra, S., Catarino, C., & Santos‐Silva, A. (2013) · Obesity Reviews · doi:10.1111/obr.12057 · Cited by 83
“(29) by performing studies in human liver cell cultures, in mice and in human volunteers concluded that IL-6 is sufficient to induce hepcidin production during inflammation and that the IL-6-hepcidin axis is responsible 774 Adipocyte role in iron metabolism S.”
BackgroundZumbrennen‐Bullough, K. B., & Babitt, J. L. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft443 · Cited by 82
“Other mediators of inflammation and infection including IL-22, type I interferon, tumor necrosis factor alpha and endoplasmic reticulum stress have also been implicated in hepcidin regulation [27, 29, 30].”
BackgroundIron Homeostasis and Its Interaction with Prolyl Hydroxylases
Mole, D. R. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2790 · Cited by 80
Springer, L., Peter, A., Poets, C. F., & Franz, A. R. (2013) · Neonatology · doi:10.1159/000353161 · Cited by 79
Demirağ, M. D., Haznedaroğlu, Ş., Sancak, B., Değertekin, C. K., Gülbahar, Ö., Öztürk, M. A., & Göker, B. (2009) · Internal Medicine · doi:10.2169/internalmedicine.48.1578 · Cited by 81
“In humans, experimental hepcidin increase, induced by IL-6 infusion, is accompanied by a decrease in SI levels (21).”
BackgroundKarl, J. P., Lieberman, H. R., Cable, S. J., Williams, K. W., Young, A., & McClung, J. P. (2010) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2010.29185 · Cited by 79
Plant-Based Dietary Practices and Socioeconomic Factors That Influence Anemia in India
Bhatnagar, R. S., & Padilla‐Zakour, O. I. (2021) · Nutrients · doi:10.3390/nu13103538 · Cited by 85
“Recent studies have exhibited the putative role of the cytokine interleukin-6 in stimulating hepcidin production [199,200].”
BackgroundHigh-throughput screening of small molecules identifies hepcidin antagonists
Fung, E., Sugianto, P., Hsu, J., Damoiseaux, R., Ganz, T., & Nemeth, E. (2013) · Molecular Pharmacology · doi:10.1124/mol.112.083428 · Cited by 78
Self-citationChung, B., Chaston, T. B., Marks, J., Srai, S. K., & Sharp, P. (2009) · Journal of Nutrition · doi:10.3945/jn.108.102905 · Cited by 78
Long-term pathological consequences of prenatal infection: beyond brain disorders
Labouesse, M. A., Langhans, W., & Meyer, U. (2015) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00087.2015 · Cited by 80
Hepcidin messenger RNA expression in human lymphocytes
Pinto, J. P., Dias, V., Zoller, H., Porto, G., Carmo, H., Carvalho, F. D., & de Sousa, M. A. B. (2010) · Immunology · doi:10.1111/j.1365-2567.2009.03226.x · Cited by 81
Graf, A. E., Lallier, S. W., Waidyaratne, G., Thompson, M. D., Tipple, T. E., Hester, M. E., Trask, A. J., & Rogers, L. K. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.08.005 · Cited by 78
“Hepcidin dysregulation is associated with inflammation and oxidative stress (Lieblein-Boff et al., 2013; Nemeth et al., 2004; Urrutia et al., 2013).”
Robertson, L. S., Iwanowicz, L. R., & Marranca, J. M. (2009) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2009.03.023 · Cited by 78
Recycling Iron in Normal and Pathological States
Beaumont, C., & Delaby, C. (2009) · Seminars in Hematology · doi:10.1053/j.seminhematol.2009.06.004 · Cited by 84
Weßels, I., & Cousins, R. J. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00179.2015 · Cited by 78
Tanaka, T., Hishitani, Y., & Ogata, A. (2014) · Biologics · doi:10.2147/btt.s37509 · Cited by 78
Tocilizumab, a humanized anti-interleukin-6 receptor antibody, for treatment of rheumatoid arthritis
Mihara, M., Ohsugi, Y., & Kishimoto (2011) · Open Access Rheumatology Research and Reviews · doi:10.2147/oarrr.s17118 · Cited by 78
Metabolismo do ferro: uma revisão sobre os principais mecanismos envolvidos em sua homeostase
Grotto, H. Z. W. (2008) · Revista Brasileira de Hematologia e Hemoterapia · doi:10.1590/s1516-84842008000500012 · Cited by 78
Emerging Roles of the Iron Chelators in Inflammation
Paola, A. D., Tortora, C., Argenziano, M., Marrapodi, M. M., & Rossi, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23147977 · Cited by 80
“Hepcidin is a protein hormone responsible for FPN1 degradation, thus inhibiting iron release by cells and determining iron accumulation in cells [15,20].”
BackgroundRichards, T., Clevenger, B., Keidan, J., Collier, T. J., Klein, A. A., Anker, S. D., & Kelly, J. D. (2015) · Trials · doi:10.1186/s13063-015-0774-2 · Cited by 78
“A key feature of ACD is a disruption of normal iron homeostasis initiated by a cytokine-mediated immune response, such as in chronic inflammatory disease, during infection or following surgery [6, 7].”
BackgroundPieracci, F. M., Henderson, P. W., Rodney, J. R. M., Holena, D. N., Genisca, A. E., Ip, I. K., Benkert, S., Hydo, L. J., Eachempati, S. R., Shou, J., et al. (2009) · Surgical Infections · doi:10.1089/sur.2008.043 · Cited by 77
Sirolimus Interferes with Iron Homeostasis in Renal Transplant Recipients
Maiorano, A., Stallone, G., Schena, A., Infante, B., Pontrelli, P., Schena, F. P., & Grandaliano, G. (2006) · Transplantation · doi:10.1097/01.tp.0000235545.49391.1b · Cited by 77
“Thus, this small peptide was suggested to play a key role in the chronic inflammation-related anemia (18, 19).”
BackgroundNot so benign haematology: anaemia of the elderly
Merchant, A. A., & Roy, C. N. (2011) · British Journal of Haematology · doi:10.1111/j.1365-2141.2011.08920.x · Cited by 78
NRF2 and Hypoxia-Inducible Factors: Key Players in the Redox Control of Systemic Iron Homeostasis
Duarte, T. L., Talbot, N. P., & Drakesmith, H. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8148 · Cited by 77
Chua, A. C. G., Klopcic, B. R. S., Ho, D. S., Fu, S. K., Forrest, C. H., Croft, K. D., Olynyk, J. K., Lawrance, I. C., & Trinder, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078850 · Cited by 76
“The inflammatory cytokine interleukin (IL)-6 increases the synthesis of liver hepcidin, a major iron-regulatory hormone central to iron homeostasis, resulting in reduced duodenal iron absorption and retention of iron in macrophages and hepatocytes promoting iron storage thus limiting the availability of iron for eryth…”
BackgroundNeurological disorders and inflammatory bowel diseases.
Casella, G., Tontini, G. E., Bassotti, G., Pastorelli, L., Villanacci, V., Spina, L., Baldini, V., & Vecchi, M. L. (2014) · PubMed Central · doi:10.3748/wjg.v20.i27.8764 · Cited by 76
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Song, S., Hua, C., Dornbors, D., Kang, R.-J., Zhao, X., Du, X., He, W., Ding, Y., & Meng, R. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01237 · Cited by 75
“During stroke-induced inflammation, various cytokines are released and affect erythropoiesis, erythropoietin (EPO) production (47, 48), inhibition of erythroid progenitors (49), and reduction in iron release (50, 51).”
BackgroundMillonig, G., Ganzleben, I., Peccerella, T., Casanovas, G., Brodziak‐Jarosz, L., Breitkopf‐Heinlein, K., Dick, T. P., Seitz, H. K., Muckenthaler, M. U., & Mueller, S. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.358911 · Cited by 78
“The hepcidin-mediated blockage of ferroportin efficiently prevents iron export to the extracellular space and is amajormechanistic pathway of the anemia of chronic disease (6).”
BackgroundAnemia of Aging: The Role of Chronic Inflammation and Cancer
Ferrucci, L., & Balducci, L. (2008) · Seminars in Hematology · doi:10.1053/j.seminhematol.2008.06.001 · Cited by 75
Persistent Iron Deficiency Anemia in Patients with Celiac Disease Despite a Gluten-Free Diet
Stefanelli, G., Viscido, A., Longo, S. A., Magistroni, M., & Latella, G. (2020) · Nutrients · doi:10.3390/nu12082176 · Cited by 79
“It has been reported that pro-inflammatory cytokines—in particular interferon-gamma (IFN-y), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)—trigger the synthesis of the iron regulatory hormone, hepcidin [26,27].”
BackgroundThe small molecule, genistein, increases hepcidin expression in human hepatocytes
Zhen, A. W., Nguyen, N. H., Gibert, Y., Motola, S., Buckett, P., Wessling-Resnick, M., Fraenkel, E., & Fraenkel, P. G. (2013) · Hepatology · doi:10.1002/hep.26490 · Cited by 74
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“Inflammatory cytokines increase the expression of hepcidin (Nemeth et al, 2004; Kemna et al, 2008), leading to a decreased absorption of iron from the intestine and a diversion of iron from the circulation into storage sites, such as the reticuloendothelial system (RES) and the liver (Weiss, 2009).”
BackgroundIron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells
Liang, W. P., & Ferrara, N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.626812 · Cited by 75
“IL-6 is expressed by TAM and neutrophils and stimulates hepcidin expression in hepatocytes (81, 82).”
BackgroundHepcidin: A novel peptide hormone regulating iron metabolism
Singh, B. M., Arora, S., Agrawal, P., & Gupta, S. (2011) · Clinica Chimica Acta · doi:10.1016/j.cca.2011.02.014 · Cited by 77
-Thalassemia: HiJAKing Ineffective Erythropoiesis and Iron Overload
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“[49] E.”
Hepcidin: Homeostasis and Diseases Related to Iron Metabolism
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Bacterial Siderophores Hijack Neutrophil Functions
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“Accordingly, the host induces hypoferremia or “anemia of inflammation” as an acute-phase response to sequester the labile iron pool (LIP; alias catalytic/reactive iron) (7).”
BackgroundIron metabolism in infections: Focus on COVID-19
Girelli, D., Marchi, G., Busti, F., & Vianello, A. (2021) · Seminars in Hematology · doi:10.1053/j.seminhematol.2021.07.001 · Cited by 75
“Nonetheless it has been recently demonstrated that feritin, particularly the H subunit, is able to stimulate the expression f pro-inflammatory cytokines by macrophages (IL-1 β , IL-6, IL-12, nd TNF- α) and also the key inflammasome player NOD-, LRR and yrin domain-containing protein 3 (NLRP3) [ 62 , 63 ].”
InfluentialIron deficiency in systemic sclerosis patients with and without pulmonary hypertension
Ruiter, G., Lanser, I., de Man, F. S., van der Laarse, W. J., Wharton, J., Wilkins, M. R., Howard, L., Noordegraaf, A. V., & Voskuyl, A. E. (2013) · Rheumatology · doi:10.1093/rheumatology/ket331 · Cited by 78
Effect of Intravenous Iron on Aerobic Capacity and Iron Metabolism in Elite Athletes
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Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer
Orlandi, R., De Bortoli, M., Ciniselli, C. M., Vaghi, E., Caccia, D., Garrisi, V., Pizzamiglio, S., Veneroni, S., Bonini, C., Agresti, R., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdt490 · Cited by 74
Lipiński, P., Styś, A., & Starzyński, R. R. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1018-1 · Cited by 76
“It might be partially explained by the fact that the birth process initiates an acute phase response in a healthy fetus/newborn, which is characterized by increased circulating levels of interleukin-6 [122], a wellknown inflammatory cytokine that is responsible for the induction of Hepc during inflammation [123].”
BackgroundMaternal hepcidin determines embryo iron homeostasis in mice
Sangkhae, V., Fisher, A. L., Chua, K. J., Ruchala, P. P., Ganz, T., & Nemeth, E. (2020) · Blood · doi:10.1182/blood.2020005745 · Cited by 73
Self-citationExercise as a mediator of hepcidin activity in athletes
Peeling, P. (2010) · European Journal of Applied Physiology · doi:10.1007/s00421-010-1594-4 · Cited by 73
Metadata
- Authors
- Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., & Ganz, T.
- Affiliations
- University of California, Los Angeles (US)
- Rigshospitalet (DK)
- Corresponding author
- Ganz, Tomas
- Venue
- Journal of Clinical Investigation
- Published
- 2004-05-01
- Volume
- 113
- Issue
- 9
- Pages
- 1271-1276
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC398432
- OpenAlex
- W2132155262
- Cited by
- 2,650
- References
- 40
- Citations by year
- 2026: 100 · 2025: 97 · 2024: 93 · 2023: 117 · 2022: 115 · 2021: 145 · 2020: 134 · 2019: 130 · 2018: 130 · 2017: 141 · 2016: 103 · 2015: 135 · 2014: 132 · 2013: 140 · 2012: 137
- FWCI
- 55.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- David Geffen School of Medicine, University of California, Los Angeles
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- interleukin-6, hepcidin, iron regulation, inflammation, cytokine signaling, liver, iron regulatory hormone
- MeSH terms
- Anemia, Animals, Cell Line, Cells, Cultured, Gene Expression Regulation, Humans, Inflammation, Iron, Kupffer Cells, Mice, Inbred C57BL, Monocytes, RNA, Messenger, Interleukin-6, Mice, Knockout, Iron Metabolism Disorders, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, Antimicrobial Cationic Peptides, Mice, Hepcidins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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