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
Krause, A., Neitz, S., Mägert, H.-J., Schulz, A., Forssmann, W.-G., Schulz-Knappe, P., & Adermann, K. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01920-7 · Cited by 1,324
Age-Associated Increased Interleukin-6 Gene Expression, Late-Life Diseases, and Frailty
Ershler, W. B., & Keller, E. T. (2000) · Annual Review of Medicine · doi:10.1146/annurev.med.51.1.245 · Cited by 1,282
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Progesterone receptor membrane component-1 regulates hepcidin biosynthesis
Li, X., Rhee, D. K., Malhotra, R., Mayeur, C., Hurst, L. A., Ager, E., Shelton, G., Kramer, Y., McCulloh, D., Keefe, D., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83831 · Cited by 112
High Fat Diet Induces Liver Steatosis and Early Dysregulation of Iron Metabolism in Rats
Meli, R., Raso, G. M., Irace, C., Simeoli, R., Pascale, A. D., Paciello, O., Pagano, T. B., Calignano, A., Colonna, A., & Santamaria, R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066570 · Cited by 115
“Other studies demonstrate that in mouse and human, IL-6 is the main cytokine responsible of hepcidin induction and hypoferremia during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia in humans [56].”
BackgroundYoung, M. F., Glahn, R. P., Ariza‐Nieto, M., Inglis, J., Olbina, G., Westerman, M. E., & O'Brien, K. O. (2008) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26589 · Cited by 112
Roy, C. N. (2010) · Hematology · doi:10.1182/asheducation-2010.1.276 · Cited by 114
Katouli, M. (2010) · PubMed Central · Cited by 112
Serum cytokines associated with severity and complications of kala-azar
Costa, D. L., Rocha, R. L., Carvalho, R. M. D. A., Neto, A. S. L., Harhay, M. O., Costa, C. H. N., Barral‐Netto, M., & Barral, A. M. P. (2013) · Pathogens and Global Health · doi:10.1179/2047773213y.0000000078 · Cited by 111
Anemia in Hodgkin's Lymphoma: The Role of Interleukin-6 and Hepcidin
Hohaus, S., Massini, G., Giachelia, M., Vannata, B., Bozzoli, V., Cuccaro, A., D'Alo', F., Larocca, L. M., Raymakers, R. A. P., Swinkels, D. W., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.6873 · Cited by 110
Anaemia of cancer: an overview of mechanisms involved in its pathogenesis
Grotto, H. Z. W. (2007) · Medical Oncology · doi:10.1007/s12032-007-9000-8 · Cited by 110
“Hepcidin’s effects on enterocytes and macrophages lead to hypoferraemia and elevated iron sequestration by macrophages, which in turn lead to iron-limited erythropoiesis and anaemia [91, 92 ].”
BackgroundCepeda-Lopez, A. C., Melse‐Boonstra, A., Zimmermann, M. B., & Herter‐Aeberli, I. (2015) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.099218 · Cited by 112
“Another study reported that leptin stimulated hepcidin mRNA production via the Janus kinase-2 signal transducer and activator of transcription-3 signaling pathway in human hepatoma cells (55), similar to the effect of IL-6 (17, 20).”
BackgroundInfluentialIron deficiency in pulmonary arterial hypertension: a potential therapeutic target
Rhodes, C. J., Wharton, J., Howard, L., Gibbs, J. S. R., Noordegraaf, A. V., & Wilkins, M. R. (2011) · European Respiratory Journal · doi:10.1183/09031936.00037711 · Cited by 109
The prevalence of anemia and iron deficiency in IBD outpatients in Scandinavia
Bager, P., Befrits, R., Wikman, O., Lindgren, S. C., Moum, B. A., Hjortswang, H., & Dahlerup, J. F. (2010) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365521.2010.533382 · Cited by 109
The “Iron”-y of Iron Overload and Iron Deficiency in Chronic Obstructive Pulmonary Disease
Cloonan, S. M., Mumby, S. E., Adcock, I. M., Choi, A. M. K., Chung, K. F., & Quinlan, G. J. (2017) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201702-0311pp · Cited by 113
“IL-6 is important in the pathogenesis of COPD and is known to regulate iron homeostasis through induction of hepcidin expression (42).”
BackgroundFrom Infection to Death: An Overview of the Pathogenesis of Visceral Leishmaniasis
Costa, C. H. N., Chang, K. P., Costa, D. L., & Cunha, F. V. M. (2023) · Pathogens · doi:10.3390/pathogens12070969 · Cited by 109
Macrophages and Iron Metabolism
Ganz, T. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.mchd-0037-2016 · Cited by 118
Self-citationIntravenous iron: From anathema to standard of care
Auerbach, M., Coyne, D., & Ballard, H. S. (2008) · American Journal of Hematology · doi:10.1002/ajh.21154 · Cited by 109
“Expression of hepcidin is induced by lipopolysaccharide and interleukin 6 and is inhibited by tumor necrosis factor alpha [58].”
BackgroundLeishmania survival in the macrophage: where the ends justify the means
Duque, G. A., & Descoteaux, A. (2015) · Current Opinion in Microbiology · doi:10.1016/j.mib.2015.04.007 · Cited by 116
“Increased expression of hepcidin is observed under inflammatory conditions and can be triggered by IL-6 [57].”
BackgroundStress Erythropoiesis is a Key Inflammatory Response
Paulson, R. F., Ruan, B., Hao, S., & Chen, Y. (2020) · Cells · doi:10.3390/cells9030634 · Cited by 113
Reduction of serum hepcidin by hemodialysis in pediatric and adult patients
Zaritsky, J., Young, B., Gales, B., Wang, H.-J., Rastogi, A., Westerman, M., Nemeth, E., Ganz, T., & Salusky, I. B. (2010) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.08161109 · Cited by 107
Self-citationInvolvement of Hepcidin in the Anemia of Multiple Myeloma
Sharma, S., Nemeth, E., Chen, Y.-H., Goodnough, J. B., Huston, A. J., Roodman, G. D., Ganz, T., & Lichtenstein, A. K. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4153 · Cited by 107
Self-citationUnexplained Anemia in the Elderly
Makipour, S., Kanapuru, B., & Ershler, W. B. (2008) · Seminars in Hematology · doi:10.1053/j.seminhematol.2008.06.003 · Cited by 107
Azab, B. N., Torbey, E., Hatoum, H. A., Singh, J., Khoueiry, G., Bachir, R. H., McGinn, J. T., McCord, D., & Lafferty, J. (2011) · Cardiology · doi:10.1159/000329920 · Cited by 107
“], others have demonstrated an association between generalized inflammatory conditions and high RDW [ , , ,”
BackgroundMolecular control of iron metabolism
Andrews, N. C. (2005) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2004.10.004 · Cited by 109
Gardenghi, S., Renaud, T. M., Meloni, A., Casu, C., Crielaard, B. J., Bystrom, L. M., Greenberg-Kushnir, N., Sasu, B. J., Cooke, K. S., & Rivella, S. (2014) · Blood · doi:10.1182/blood-2013-08-521625 · Cited by 107
Pathophysiology of anemia and erythrocytosis
Hodges, V. M., Rainey, S., Lappin, T. R. J., & Maxwell, A. P. (2007) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2007.06.006 · Cited by 118
“[28] Nemeth E, Rivera S, Gabayan V, et al.”
BackgroundTraining Surface and Intensity: Inflammation, Hemolysis, and Hepcidin Expression
PEELING, P., DAWSON, B., GOODMAN, C., LANDERS, G., WIEGERINCK, E. T., SWINKELS, D. W., & TRINDER, D. (2009) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e318192ce58 · Cited by 107
Hepcidin and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload
Barisani, D., Pelucchi, S., Mariani, R., Galimberti, S., Trombini, P., Fumagalli, D., Meneveri, R., Nemeth, E., Ganz, T., & Piperno, A. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.03.011 · Cited by 111
“Hepatic hepcidin production is modulated by different influences: circulating iron and iron stores, erythropoietic activity, hypoxia and inflammatory stimuli that act through pathways involving IL-6, other cytokines, and bone morphogenetic proteins (BMPs) [18–26].”
BackgroundSelf-citationAnemia in COPD: A Systematic Review of the Prevalence, Quality of Life, and Mortality
Yohannes, A. M., & Ershler, W. B. (2011) · Respiratory Care · doi:10.4187/respcare.01002 · Cited by 107
Erythroferrone: An Erythroid Regulator of Hepcidin and Iron Metabolism
Coffey, R., & Ganz, T. (2018) · HemaSphere · doi:10.1097/hs9.0000000000000035 · Cited by 112
Self-citationIsaacs, J. D., Harari, O., Kobold, U., Lee, J. S., & Bernasconi, C. (2013) · Arthritis Research & Therapy · doi:10.1186/ar4397 · Cited by 105
“Hepcidin, ferritin and haptoglobin are produced in the liver as acutephase reactants, and their expression is dependent on interleukin-6 (IL-6) signalling [3,7,8].”
BackgroundTussing‐Humphreys, L. M., Nemeth, E., Fantuzzi, G., Freels, S., Holterman, A. L., Galvani, C., Ayloo, S., Vitello, J., & Braunschweig, C. (2010) · Obesity · doi:10.1038/oby.2009.490 · Cited by 105
“14) and serum hepcidin, and poorer iron status (10,38).”
BackgroundSelf-citationEmerging therapeutic targets for treatment of leishmaniasis
Sundar, S., & Singh, B. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1472241 · Cited by 109
“receptor [246] which can be selectively targeted for therapeu-”
BackgroundHepcidin: Iron-hormone and anti-microbial peptide
Falzacappa, M. V. V., & Muckenthaler, M. U. (2005) · Gene · doi:10.1016/j.gene.2005.07.020 · Cited by 109
Sutherland, B. J. G., Koczka, K. W., Yasuike, M., Jantzen, S. G., Yazawa, R., Koop, B. F., & Jones, S. R. M. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-200 · Cited by 107
“Hepcidin-1 regulates iron homeostasis by preventing export of iron from cells into the blood [54] and is induced by interleukin-6 during inflammation [55], by endoplasmic reticulum stress [56] or as part of a type II acute phase response [57].”
BackgroundIncreased hepcidin expression in colorectal carcinogenesis
Ward, D. G., Roberts, K., Brookes, M., Joy, H., Martin, A., Ismail, T., Spychal, R., Iqbal, T. H., & Tselepis, C. (2008) · World Journal of Gastroenterology · doi:10.3748/wjg.14.1339 · Cited by 105
Kreiner, F. F., Kraaijenhof, J. M., von Herrath, M., Hovingh, G. K., & von Scholten, B. J. (2022) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2022.2045952 · Cited by 115
How reliable an indicator of inflammation is myeloperoxidase activity?
Faith, M., Sukumaran, A., Pulimood, A. B., & Jacob, M. (2008) · Clinica Chimica Acta · doi:10.1016/j.cca.2008.06.016 · Cited by 104
Li, H., Rose, M. J., Tran, L., Zhang, J., Miranda, L. P., James, C. A., & Sasu, B. J. (2009) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/j.vascn.2009.02.004 · Cited by 104
Obesity during pregnancy and fetal iron status: is Hepcidin the link?
Dao, M. C., Sen, S., Iyer, C., Klebenov, D., & Meydani, S. N. (2012) · Journal of Perinatology · doi:10.1038/jp.2012.81 · Cited by 107
“Specifically obesity leads to increased interleukin (IL)-6 and IL-1 levels which upregulate hepcidin (10-12).”
BackgroundIron Homeostasis During Pregnancy: Maternal, Placental, and Fetal Regulatory Mechanisms
Sangkhae, V., Fisher, A. L., Ganz, T., & Nemeth, E. (2023) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-061021-030404 · Cited by 112
“In general, cytokine-driven increases in hepcidin and consequent hypoferremia (98) are important host defense mechanisms to prevent the spread of pathogenic bacteria by limiting iron availability and, in particular, decreasing the concentration of NTBI, a form highly accessible to many pathogens…”
BackgroundSelf-citationChia, Y. C., Kieneker, L. M., van Hassel, G., Binnenmars, S. H., Nolte, I. M., van Zanden, J. J., van der Meer, P., Navis, G. J., Voors, A. A., Bakker, S. J. L., et al. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.120.018549 · Cited by 115
Mitochondrial Mayhem: The Mitochondrion as a Modulator of Iron Metabolism and Its Role in Disease
Huang, M. L.-H., Lane, D. J. R., & Richardson, D. R. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.3921 · Cited by 103
“Hepcidin may also be induced by in-flammatory cytokines such as interleukin-6 (80, 100).”
Martín, S., Zou, J., Houlihan, D. F., & Secombes, C. J. (2007) · BMC Genomics · doi:10.1186/1471-2164-8-150 · Cited by 103
Corradini, E., Rozier, M., Meynard, D., Odhiambo, A., Lin, H. Y.-F., Feng, Q., Migas, M. C., Britton, R. S., Babitt, J. L., & Fleming, R. E. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.077 · Cited by 102
Iron metabolism and iron deficiency anemia in women
Cappellini, M. D., Santini, V., Braxs, C., & Shander, A. (2022) · Fertility and Sterility · doi:10.1016/j.fertnstert.2022.08.014 · Cited by 111
Zhu, B., McLaughlin, S. K., Na, R., Liu, J., Cui, Y., Martin, C., Kimura, A., Robinson, G. W., Andrews, N. C., & Hennighausen, L. G. (2008) · Blood · doi:10.1182/blood-2007-12-127480 · Cited by 107
de Francisco, Á. L. M., Stenvinkel, P., & Vaulont, S. (2008) · NDT Plus · doi:10.1093/ndtplus/sfn176 · Cited by 101
“The IL-6 inflammatory cytokine, released during the inflammatory process, was shown to correlate with dramatically increased hepcidin gene expression both in mice and humans [62].”
BackgroundThe effect of central obesity on inflammation, hepcidin, and iron metabolism in young women
Stoffel, N. U., El-Mallah, C. A., Herter‐Aeberli, I., Bissani, N., Wehbe, N., Obeid, O., & Zimmermann, M. B. (2020) · International Journal of Obesity · doi:10.1038/s41366-020-0522-x · Cited by 104
“High concentrations of circulating hepcidin reduce ferroportin-mediated export of iron from reticuloendothelial macrophages and duodenal enterocytes, resulting in iron sequestration, hypoferremia, and decreased dietary iron absorption [8, 40].”
BackgroundDistinct patterns of hepcidin and iron regulation during HIV-1, HBV, and HCV infections
Armitage, A. E., Stacey, A. R., Giannoulatou, E., Marshall, E., Sturges, P., Chatha, K., Smith, N. M. G., Huang, X., Xu, X., Pasricha, S.-R., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1402351111 · Cited by 101
“Proc Natl Acad Sci USA 76(5):2438–2441.”
Maternal modifiers of the infant gut microbiota: Metabolic consequences
Mulligan, C. M., & Friedman, J. E. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0303 · Cited by 101
Biochemistry and Biomarkers of Inflamed Patients: Why Look, What to Assess
Kaysen, G. A. (2009) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.03090509 · Cited by 100
“(74) and macrophages (73), essentially preventing gut absorp-”
BackgroundAnemia of chronic disease and defective erythropoietin production in patients with celiac disease
Bergamaschi, G., Markopoulos, K., Albertini, R., Sabatino, A. D., Biagi, F., Ciccocioppo, R., Arbustini, E., & Corazza, G. R. (2008) · Haematologica · doi:10.3324/haematol.13255 · Cited by 102
“Serum ferritin (mg/L) 60±236 76±130 Males: 15-250 (2-1680) (6-476) Females: 10-150”
The Ins and Outs of Iron Homeostasis
Donovan, A., Roy, C. N., & Andrews, N. C. (2006) · Physiology · doi:10.1152/physiol.00052.2005 · Cited by 101
Hepcidin Is Down‐Regulated in Alcohol Loading
Ohtake, T., Saito, H., Hosoki, Y., Inoue, M., Miyoshi, S., Suzuki, Y., Fujimoto, Y., & Kohgo, Y. (2007) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2006.00279.x · Cited by 100
Ohsugi, Y. (2007) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.30.2001 · Cited by 100
Hepcidin in Anemia and Inflammation in Chronic Kidney Disease
Małyszko, J., & Myśliwiec, M. (2007) · Kidney & Blood Pressure Research · doi:10.1159/000098522 · Cited by 99
“showed that hepcidin injection results in a dose-dependent in serum iron. Conversely, iron ingestion in humans induced hepcidin secretion in urine [”
BackgroundThe Role of Fibroblast Growth Factor 23 in Inflammation and Anemia
Czaya, B. A., & Faul, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174195 · Cited by 101
Genetics of iron regulation and the possible role of iron in Parkinson's disease
Rhodes, S. L., & Ritz, B. R. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.07.001 · Cited by 103
Red Blood Cell Clearance in Inflammation
Straat, M., van Bruggen, R., de Korte, D., & Juffermans, N. P. (2012) · Transfusion Medicine and Hemotherapy · doi:10.1159/000342229 · Cited by 99
The iron-regulatory hormone hepcidin: A possible therapeutic target?
Rochette, L., Gudjoncik, A., Guénancia, C., Zeller, M., Cottin, Y., & Vergely, C. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.09.004 · Cited by 104
Anemia of chronic disease: A unique defect of iron recycling for many different chronic diseases
Poggiali, E., Amicis, M. M. D., & Motta, I. (2013) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2013.07.011 · Cited by 104
“Experiments in humans have demonstrated that the infusion of IL-6 in healthy volunteers rapidly induces hepcidin synthesis, and is quickly followed by hypoferremia and a decrease in transferrin saturation [43].”
BackgroundBiomarkers for Lupus Nephritis
Rovin, B. H., & Zhang, X. (2009) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.03530509 · Cited by 98
“the anemia of chronic inflammation through its ability to inhibit iron release from macrophages and gut epithelium (37,38).”
BackgroundGender-related variations in iron metabolism and liver diseases
Harrison-Findik, D. D. (2010) · World Journal of Hepatology · doi:10.4254/wjh.v2.i8.302 · Cited by 105
Investigation of iron deficiency anaemia
Bouri, S., & Martin, J. (2018) · Clinical Medicine · doi:10.7861/clinmedicine.18-3-242 · Cited by 98
Casper, C., Chaturvedi, S., Munshi, N., Wong, R., Qi, M., Schaffer, M., Bandekar, R., Hall, B., van de Velde, H., Vermeulen, J., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0134 · Cited by 97
“Neutralization of IL6 by siltuximab is hypothesized to decrease hepcidin releasing sequestered iron leading to improvement in hemoglobin levels (32).”
BackgroundTraglia, M., Girelli, D., Biino, G., Campostrini, N., Corbella, M., Sala, C., Masciullo, C., Viganò, F., Buetti, I., Pistis, G., et al. (2011) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2011-100061 · Cited by 97
“Hepcidin controls the surface expression of the iron exporter ferroportin on enterocytes and iron recycling macrophages.(3) Genetic disorders of the hepcidineferroportin pathway lead to opposite conditions.”
BackgroundWeir, M. R. (2021) · American Journal of Nephrology · doi:10.1159/000516901 · Cited by 101
Hepcidin: clinical utility as a diagnostic tool and therapeutic target
Coyne, D. W. (2011) · Kidney International · doi:10.1038/ki.2011.141 · Cited by 97
Iron Status and Gestational Diabetes—A Meta-Analysis
Kataria, Y., Wu, Y., Horskjær, P. D. H., Mandrup-Poulsen, T. R., & Ellervik, C. (2018) · Nutrients · doi:10.3390/nu10050621 · Cited by 99
“Hepcidin has been associated with inflammatory states in humans [46,47].”
BackgroundCavaliere, G., Cimmino, F., Trinchese, G., Catapano, A., Petrella, L., D’Angelo, M., Lucchin, L., & Mollica, M. P. (2023) · Antioxidants · doi:10.3390/antiox12061172 · Cited by 104
“In fact, in overweight and obese people, both serum hepcidin and interleukin-6 are significantly higher than in normal-weight people [149,158].”
BackgroundLeenstra, T., Acosta, L. P., LANGDON, G. C., MANALO, D. L., Su, L., Olveda, R. M., McGarvey, S. T., Kurtis, J. D., & Friedman, J. F. (2006) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/83.2.371 · Cited by 96
“Recent evidence has pointed to IL-6 as a mediator of functional ID (ie, iron trapping in the reticuloendothelial system), one of the processes central to the etiology of AI (22).”
Gardenghi, S., Grady, R. W., & Rivella, S. (2010) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2010.08.003 · Cited by 98
“Hepcidin is up regulated in response to iron overload (57) and inflammation (58-61), and down regulated by erythropoietic stimuli such as anemia, hypoxia or EPO synthesis/ administration (58,62,63).”
BackgroundIron metabolism: current facts and future decisions
Tandara, L., & Salamunić, I. (2012) · Biochemia Medica · doi:10.11613/bm.2012.034 · Cited by 102
Hematological alterations in diabetic rats
Mahmoud, A. M. (2013) · EXCLI journal · doi:10.17877/de290r-7264 · Cited by 96
Leenstra, T., Coutinho, H. M., Acosta, L. P., LANGDON, G. C., Su, L., Olveda, R. M., McGarvey, S. T., Kurtis, J. D., & Friedman, J. F. (2006) · Infection and Immunity · doi:10.1128/iai.00757-06 · Cited by 95
“First, proinflammatory cytokines, in particular TNF- , IL-1, and IL-6, cause anorexia (11, 26) and thus lead to a decreased intake of dietary iron.”
BackgroundInfluentialHematological alterations in diabetic rats - Role of adipocytokines and effect of citrus flavonoids.
Mahmoud, A. M. (2013) · EXCLI journal · Cited by 95
New insights into the links between hypoxia and iron homeostasis
Renassia, C., & Peyssonnaux, C. (2019) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000494 · Cited by 98
Cumulative effects of consecutive running sessions on hemolysis, inflammation and hepcidin activity
Peeling, P., Dawson, B., Goodman, C., Landers, G., Wiegerinck, E. T., Swinkels, D. W., & Trinder, D. (2009) · European Journal of Applied Physiology · doi:10.1007/s00421-009-0988-7 · Cited by 95
“However, the impact stress of heel strike during running has been identified as the largest contributor to the destruction of red blood cells, due to a force-dependent relationship between heelstrike and the degree of hemolysis experienced ( Miller et al. 1988; Telford et al. 2003).”
BackgroundHepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53
Weizer‐Stern, O., Adamsky, K., Margalit, O., Ashur‐Fabian, O., Givol, D., Amariglio, N., & Rechavi, G. (2007) · British Journal of Haematology · doi:10.1111/j.1365-2141.2007.06638.x · Cited by 94
“…regulator of iron metabolism, is transcriptionally activated by p53 Hepcidin regulates iron efflux from enterocytes and other cells, such as hepatocytes and reticuloendothelial macrophages, by internalisation and degradation of ferroportin, the iron exporter of these cells (Nemeth et al, 2004a).”
BackgroundInteracting signals in the control of hepcidin expression
Darshan, D., & Anderson, G. J. (2009) · BioMetals · doi:10.1007/s10534-008-9187-y · Cited by 95
Pieracci, F. M., Stovall, R. T., Jaouen, B. M., Rodil, M., Cappa, A., Burlew, C. C., Holena, D. N., Maier, R. V., Berry, S. D., Jurkovich, J., et al. (2014) · Critical Care Medicine · doi:10.1097/ccm.0000000000000408 · Cited by 94
“However, many critically ill patients are unable to tolerate enteral medications, and the inflammatory response associated with critical illness impairs enteral absorption of iron (15).”
BackgroundIron Homeostasis in the Lungs—A Balance between Health and Disease
Neves, J., Haider, T., Gassmann, M., & Muckenthaler, M. U. (2019) · Pharmaceuticals · doi:10.3390/ph12010005 · Cited by 94
“, IL6) induce the expression of the iron-regulated hormone hepcidin that degrades the iron exporter FPN located in macrophages and duodenal enterocytes, thereby reducing iron export to the circulation [24].”
BackgroundMomelotinib: an emerging treatment for myelofibrosis patients with anemia
Chifotides, H. T., Bose, P., & Verstovšek, S. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01157-4 · Cited by 99
“produced during inflammation [79, 80]; IL-6 acts through the JAK-STAT3 pathway in hepatocytes (Fig.”
BackgroundXu, Y., Alfaro-Magallanes, V. M., & Babitt, J. L. (2020) · British Journal of Haematology · doi:10.1111/bjh.17252 · Cited by 99
“The major signalling pathway for infectious organisms to induce hepcidin is by stimulating production of interleukin 6 (IL-6), which upregulates hepcidin transcription via the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway (Fig 2).(75,76) Other cytokines such as IL-22, IL-1b, and a…”
BackgroundNutritional Aspects of Iron in Health and Disease
Charlebois, E., & Pantopoulos, K. (2023) · Nutrients · doi:10.3390/nu15112441 · Cited by 99
“Hepcidin is transcriptionally induced in response to iron or inflammatory cues via BMP/SMAD and IL-6/STAT3 signaling, respectively [30,31].”
BackgroundHepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia
Michels, K. R., Zhang, Z., Bettina, A. M., Cagnina, R. E., Stefanova, D., Burdick, M. D., Vaulont, S., Nemeth, E., Ganz, T., & Mehrad, B. (2017) · JCI Insight · doi:10.1172/jci.insight.92002 · Cited by 93
Self-citationDaher, R., Kannengiesser, C., Houamel, D., Lefèbvre, T., Bardou‐Jacquet, E., Ducrot, N., de Kerguenec, C., Jouanolle, A., Robréau, A.-M., Oudin, C., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.10.049 · Cited by 98
“Hepcidin synthesis is also induced by inflammatory signals such as IL-6 and plays a major role in the anemia of chronic diseases [8,9].”
BackgroundRegulation of hepcidin expression at high altitude
Talbot, N. P., Lakhal, S., Smith, T. G., Privat, C., Nickol, A. H., Rivera-Ch, M., León-Velarde, F., Dorrington, K. L., Mole, D. R., & Robbins, P. A. (2012) · Blood · doi:10.1182/blood-2011-03-341776 · Cited by 93
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“Iron overload, infection and inflammatory cytokines are well recognized as factors leading to increased hepatic hepcidin expression [3,7,8].”
BackgroundInterleukin-6 in renal disease and therapy
Jones, S. A., Fraser, D. J., Fielding, C. A., & Jones, G. W. (2014) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfu233 · Cited by 94
Iron in Health and Disease: An Update
Lal, A. (2019) · The Indian Journal of Pediatrics · doi:10.1007/s12098-019-03054-8 · Cited by 92
“interleukin-6 (IL-6) which binds to its receptor on hepatocytes to activate STAT3 and increase hepcidin synthesis [9].”
BackgroundThe Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders
Xu, Y., Jia, B., Li, J., Li, Q., & Luo, C. (2024) · Antioxidants · doi:10.3390/antiox13040395 · Cited by 92
“Common inflammatory factors released during neuroinflammation exhibit close associations with proteins that govern cellular iron metabolism and lipid metabolism [11].”
BackgroundThe Effects of Acute Exercise Bouts on Hepcidin in Women
Newlin, M. K., Williams, S., McNamara, T., Tjalsma, H., Swinkels, D. W., & Haymes, E. M. (2012) · International Journal of Sport Nutrition and Exercise Metabolism · doi:10.1123/ijsnem.22.2.79 · Cited by 91
Understanding How Minerals Contribute to Optimal Immune Function
Ştefanache, A., Lungu, I. I., Butnariu, I.-A., Călin, G., Guțu, C., Marcu, C., Grierosu, C., Goroftei, E. R. B., Duceac, L.-D., Dabija, M. G., et al. (2023) · Journal of Immunology Research · doi:10.1155/2023/3355733 · Cited by 99
“Proin fl ammatory signals like IL-6 or PAMP cause the synthesis of macrophage hepcidin, which appears to be resistant to iron status [151 – 154].”
BackgroundThe function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation
Liu, S., Suragani, R. N. V. S., Wang, F., Han, A., Zhao, W., Andrews, N. C., & Chen, J.-J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32084 · Cited by 91
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Lepanto, M. S., Rosa, L., Cutone, A., Conte, M. P., Paesano, R., & Valenti, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02123 · Cited by 91
de Mast, Q., Nadjm, B., Reyburn, H., Kemna, E. H. J. M., Amos, B., Laarakkers, C. M. M., Silalye, S., Verhoef, H., Sauerwein, R. W., Swinkels, D. W., et al. (2009) · The Journal of Infectious Diseases · doi:10.1086/595790 · Cited by 89
“regulation, and inflammation-related regulation [7, 8].”
InfluentialThaunat, O., Beaumont, C., Chatenoud, L., Lechaton, S., Mamzer, M., Varet, B. R., Kreis, H., & Morélon, E. (2005) · Transplantation · doi:10.1097/01.tp.0000179106.07382.6a · Cited by 89
“IL6 has also been reported to have a role in ACIS pathophysiology by stimulating the hepcidin production by the liver (19).”
BackgroundRoe, M. A., Spinks, C. A., Heath, A. M., Harvey, L. J., Foxall, R., Wimperis, J. Z., Wolf, C., & Fairweather‐Tait, S. J. (2007) · British Journal Of Nutrition · doi:10.1017/s0007114507336829 · Cited by 89
“Hepcidin influences iron absorption through direct binding to ferroportin at the basolateral membrane, leading to decreased export of cellular iron (Nemeth et al. 2004a).”
BackgroundMethod
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
About these checks
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
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