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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Hepcidin—A Peptide Hormone at the Interface of Innate Immunity and Iron Metabolism
Ganz, T. (2006) · Springer eBooks · doi:10.1007/3-540-29916-5_7 · Cited by 147
Self-citationWard, R. J., Crichton, R. R., Taylor, D. L., Corte, L., Srai, S. K., & Dexter, D. T. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0479-3 · Cited by 150
“In both humans and mice, this is indirect and mediated by macrophage production of cytokines IL-6 and IL-1 (Lee et al. 2004, 2005; Nemeth et al. 2004), as well as STAT3 (Fig.”
BackgroundEvidence for differential effects of hepcidin in macrophages and intestinal epithelial cells
Chaston, T., Chung, B., Mascarenhas, M., Marks, J., Patel, B., Srai, S. K., & Sharp, P. (2008) · Gut · doi:10.1136/gut.2007.131722 · Cited by 145
A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin
Kim, A., Fung, E., Parikh, S. G., Valore, E. V., Gabayan, V., Nemeth, E., & Ganz, T. (2014) · Blood · doi:10.1182/blood-2013-08-521419 · Cited by 145
Self-citationMacciò, A., Madeddu, C., Massa, D., Mudu, M. C., Lusso, M. R., Gramignano, G., Serpe, R., Melis, G. B., & Mantovani, G. (2005) · Blood · doi:10.1182/blood-2005-01-0160 · Cited by 144
Anderson, G., & Maes, M. H. J. (2012) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.06.014 · Cited by 146
“therefore interact with prenatal infection (Nemeth et al., 2004).”
Diagnosis and management of anaemia of chronic disease: current status
Cullis, J. (2011) · British Journal of Haematology · doi:10.1111/j.1365-2141.2011.08741.x · Cited by 144
“Once bound to ferroportin, the ligand-receptor complex is internalized and degraded, and cellular iron export ceases (Nemeth et al, 2004b).”
BackgroundMethodInfluentialAnti‐interleukin‐6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases
Tanaka, T., Narazaki, M., & Kishimoto, T. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.03.023 · Cited by 148
“Induction of hepcidin by IL-6 in liver causes hypoferremia by blocking iron transporter ferroportin 1 on gut, resulting in anemia of inflammation [13].”
BackgroundHepcidin expression and iron transport in alveolar macrophages
Nguyen, N.-B., Callaghan, K. D., Ghio, A. J., Haile, D. J., & Yang, F. (2006) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00484.2005 · Cited by 143
“Although HAMP synthesis has been shown to be regulated by IL-1 and IL-6 in hepatocytes (20, 23, 31), none of the cytokines in our studies, including IL-1, IL-6, TNF- , and interferon- , had a significant effect on the expression of HAMP in AM.”
BackgroundSong, S.-N. J., Iwahashi, M., Tomosugi, N., Uno, K., Yamana, J., Yamana, S., Isobe, T., Ito, H., Kawabata, H., & Yoshizaki, K. (2013) · Arthritis Research & Therapy · doi:10.1186/ar4323 · Cited by 143
“In contrast, TNFα does not induce, but rather inhibits, hepcidin expression in vitro [22].”
BackgroundResultMacrophage Iron, Hepcidin, and Atherosclerotic Plaque Stability
Sullivan, J. L. (2007) · Experimental Biology and Medicine · doi:10.3181/0703-mr-54 · Cited by 147
Hemochromatosis: Genetics and Pathophysiology
Beutler, E. (2005) · Annual Review of Medicine · doi:10.1146/annurev.med.57.121304.131310 · Cited by 142
Physiological effects of modulating the interleukin-6 axis
Schett, G. A. (2018) · Rheumatology · doi:10.1093/rheumatology/kex513 · Cited by 148
van Santen, S., van Dongen-Lases, E. C., de Vegt, F., Laarakkers, C. M., van Riel, P. L. C. M., van Ede, A. E., & Swinkels, D. W. (2011) · Arthritis & Rheumatism · doi:10.1002/art.30623 · Cited by 142
Evaluation of standard liver volume formulae for Chinese adults
Shi, Z., Yan, L., Li, B., & Wen, T. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.3462 · Cited by 140
Porto, G. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i35.4707 · Cited by 140
Estrogen Regulates Hepcidin Expression via GPR30-BMP6-Dependent Signaling in Hepatocytes
Ikeda, Y., Tajima, S., Izawa-Ishizawa, Y., Kihira, Y., Ishizawa, K., Tomita, S., Tsuchiya, K., & Tamaki, T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040465 · Cited by 140
“Hepcidin is regulated by various factors, including inflammation and cytokines such as interleukin-6 (IL-6) [8].”
BackgroundInfluentialIL-6 Revisited: From Rheumatoid Arthritis to CAR T Cell Therapy and COVID-19
Kishimoto, T., & Kang, S. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101220-023458 · Cited by 140
Nutritional interventions and the IL‐6 response to exercise
Hennigar, S. R., McClung, J. P., & Pasiakos, S. M. (2017) · The FASEB Journal · doi:10.1096/fj.201700080r · Cited by 148
Iron and anemia in human biology: a review of mechanisms
Handelman, G. J., & Levin, N. W. (2008) · Heart Failure Reviews · doi:10.1007/s10741-008-9086-x · Cited by 143
“The most characteristic and widely applied assay of the inflammatory response is plasma CRP, which increases in response to pro-inflammatory cytokines such as IL-6, Il-1, and TNF-alpha [35].”
InfluentialWoodman, R., Ferrucci, L., & Guralnik, J. M. (2005) · Current Opinion in Internal Medicine · doi:10.1097/01.moh.0000154030.13020.85 · Cited by 139
Zughaier, S. M., Shafer, W. M., & Stephens, D. S. (2005) · Cellular Microbiology · doi:10.1111/j.1462-5822.2005.00549.x · Cited by 138
“In addition, several lines of evidence have shown that AMP are signalling and chemotactic molecules that connect the innate and adaptive immune responses (Baeuerle et al., 1996; Kaul and Forman, 1996; Tang et al., 2002; Bowdish et al., 2004; Nemeth et al., 2004).”
BackgroundLiu, J. L., Sun, B., Yin, H.-J., & Liu, S. (2016) · Medicine · doi:10.1097/md.0000000000003150 · Cited by 141
“It is contributed to IL-6 and IL-22 productions, but not IL-1b and tumor necrosis factor-a (TNF-a).(43,44) Further research confirmed that Hamp promoter contains Stat3-binding site, and siRNA-mediated Stat3 knockdown significantly decreased hepcidin transcription.”
BackgroundRossi, J., Lu, Z. Y., Massart, C., & Levón, K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.595722 · Cited by 140
Lee, J., & Hyun, D. (2023) · Antioxidants · doi:10.3390/antiox12040918 · Cited by 142
“IL-6 increases hepcidin and accumulates iron in the intracellular space while promoting the degradation of FPN1 by hepcidin [49,50].”
BackgroundGenetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin
Pietrangelo, A. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.06.045 · Cited by 136
Biomarkers of lupus nephritis determined by serial urine proteomics
Zhang, X., Jin, M., Wu, H., Nadasdy, T., Nadasdy, G., Harris, N., Green-Church, K., Nagaraja, H., Birmingham, D. J., Yu, C.-Y., et al. (2008) · Kidney International · doi:10.1038/ki.2008.316 · Cited by 136
Novel urine hepcidin assay by mass spectrometry
Kemna, E., Tjalsma, H., Laarakkers, C. M., Nemeth, E., Willems, H. L., & Swinkels, D. W. (2005) · Blood · doi:10.1182/blood-2005-05-1873 · Cited by 135
Self-citationIron deficiency in the elderly population, revisited in the hepcidin era
Busti, F., Campostrini, N., Martinelli, N., & Girelli, D. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00083 · Cited by 137
“Since the focus of this article is on etiology, diagnosis, and management of the absolute ID in elderly, the readers are referred to others excellent reviews for details on the functional ID syndromes (Goodnough et al., 2010, Goodnough, 2012; Auerbach et al., 2013a).”
BackgroundIron-regulatory protein hepcidin is increased in female athletes after a marathon
Röcker, L., Meier-Buttermilch, R., Brechtel, L. M., Nemeth, E., & Ganz, T. (2005) · European Journal of Applied Physiology · doi:10.1007/s00421-005-0055-y · Cited by 134
“In some long distance female runners, chronic increase in hepcidin could contribute to the development of ID through the inhibitory effects of hepcidin on intestinal iron absorption and on the release of iron from macrophages that recycle senescent red blood cells (Nemeth et al. 2004).”
BackgroundMethodInfluentialSelf-citationViatte, L., & Vaulont, S. (2009) · Biochimie · doi:10.1016/j.biochi.2009.06.012 · Cited by 140
David, S., Jhelum, P., Ryan, F., Jeong, S. Y., & Kroner, A. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0218 · Cited by 134
In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2
Maes, K., Nemeth, E., Roodman, G. D., Huston, A., Esteve, F., Freytes, C., Callander, N., Katodritou, E., Tussing-Humphreys, L., Rivera, S., et al. (2010) · Blood · doi:10.1182/blood-2010-03-274571 · Cited by 132
Self-citationWang, J. K., & Klein, H. G. (2009) · Vox Sanguinis · doi:10.1111/j.1423-0410.2009.01223.x · Cited by 133
Mitchell, C. J., Shawki, A., Ganz, T., Nemeth, E., & Mackenzie, B. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00348.2013 · Cited by 132
Self-citationCauses and Significance of Markedly Elevated Serum Ferritin Levels in an Academic Medical Center
Moore, C., Ormseth, M. J., & Fuchs, H. A. (2013) · JCR Journal of Clinical Rheumatology · doi:10.1097/rhu.0b013e31829ce01f · Cited by 132
Whole cigarette smoke condensates induce ferroptosis in human bronchial epithelial cells
Park, E., Park, Y.-J., Lee, S. J., Lee, K., & Yoon, C. (2018) · Toxicology Letters · doi:10.1016/j.toxlet.2018.12.007 · Cited by 131
The Regulation of Hepcidin and Its Effects on Systemic and Cellular Iron Metabolism
Fleming, M. D. (2008) · Hematology · doi:10.1182/asheducation-2008.1.151 · Cited by 134
Hepcidin agonists as therapeutic tools
Casu, C., Nemeth, E., & Rivella, S. (2018) · Blood · doi:10.1182/blood-2017-11-737411 · Cited by 136
Self-citationTransition metal ions at the crossroads of mucosal immunity and microbial pathogenesis
Diaz-Ochoa, V. E., Jellbauer, S., Klaus, S., & Raffatellu, M. (2014) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2014.00002 · Cited by 129
Kalinowski, D. S., Stefani, C., Toyokuni, S., Ganz, T., Anderson, G. J., Subramaniam, V. N., Trinder, D., Olynyk, J. K., Chua, A. C. G., Jansson, P. J., et al. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.01.026 · Cited by 131
“The iron limitation is primarily due to an increase in circulating levels of the inflammatory cytokine, interleukin-6, that up-regulates expression of hepcidin, which is a type II acute-phase reactant [105, 106].”
BackgroundSelf-citationPakbaz, Z., Fischer, R., Fung, E. B., Nielsen, P., Harmatz, P., & Vichinsky, E. P. (2007) · Pediatric Blood & Cancer · doi:10.1002/pbc.21275 · Cited by 128
“These higher intracellular iron concentrations will lead to increased ferritin synthesis and secretion [16].”
BackgroundRodriguez, R., Jung, C.-L., Gabayan, V., Deng, J. C., Ganz, T., Nemeth, E., & Bulut, Y. (2014) · Infection and Immunity · doi:10.1128/iai.00983-13 · Cited by 127
“As standard mouse chow contains high iron content ( 300 ppm) and causes near-maximal hepcidin expression (10), mice at 6 weeks of age were placed on a low-iron diet (4 ppm; Harlan Teklad, Indianapolis, IN)”
BackgroundMethodInfluentialSelf-citationAssociation between depression and anemia in otherwise healthy adults
Vulser, H., Wiernik, E., Hoertel, N., Thomas, F., Pannier, B., Czernichow, S., Hanon, O., Simon, T., Simon, J.-M., Danchin, N., et al. (2016) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12595 · Cited by 131
“It has been linked to lowered iron availability, altered erythrocyte production, and shorter erythrocyte life span (24, 60).”
BackgroundIron metabolism and related genetic diseases: A cleared land, keeping mysteries
Brissot, P., & Loréal, O. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.11.009 · Cited by 131
“One major mechanism is represented by inflammation which stimulates hepcidin production through the interleukin-6(IL-6)(48) (and IL-22(49))-STAT3 (signal transducer and activator of transcription) signalling pathway, and through activin B which likely implicates the BMP-SMAD pathway(50).”
BackgroundThe Pathogenesis of Cardiomyopathy in Friedreich Ataxia
Koeppen, A. H., Ramirez, R. L., Becker, A. B., Bjork, S. T., Levi, S., Santambrogio, P., Parsons, P. J., Kruger, P. C., Yang, K. X., Feustel, P. J., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116396 · Cited by 126
Burden, R. J., Morton, K., Richards, T., Whyte, G. P., & Pedlar, C. R. (2015) · British Journal of Sports Medicine · doi:10.1136/bjsports-2014-093624 · Cited by 125
Hepcidin and the BMP-SMAD pathway: An unexpected liaison
Silvestri, L., Nai, A., Dulja, A., & Pagani, A. (2019) · Vitamins and hormones · doi:10.1016/bs.vh.2019.01.004 · Cited by 136
Aflatoxin Exposure During Pregnancy, Maternal Anemia, and Adverse Birth Outcomes
Smith, L. E., Prendergast, A. J., Turner, P. C., Humphrey, J. H., & Stoltzfus, R. J. (2017) · American Journal of Tropical Medicine and Hygiene · doi:10.4269/ajtmh.16-0730 · Cited by 125
“IL-6—which has shown to be upregulated by aflatoxin exposure(24)—increases hepcidin production, which decreases iron absorption and iron release from macrophages.(70) However, further human and animal studies are needed to test these hypotheses.”
BackgroundGangat, N., & Wolanskyj, A. P. (2013) · Seminars in Hematology · doi:10.1053/j.seminhematol.2013.06.006 · Cited by 127
Horiguchi, H., Oguma, E., & Kayama, F. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr100 · Cited by 126
“…hormone (Pigeon et al., 2001), binds and downregulates ferroportin1 expressed in enterocytes and macrophages: in iron deficiency, the production is decreased, resulting in increases of duodenal iron absorption and macrophage iron release through ferroportin1 accumulation (Nemeth et al., 2004b).”
BackgroundAnemia of chronic disease: pathophysiology and laboratory diagnosis.
THOMAS, C., & THOMAS, L. (2005) · Laboratory Hematology · doi:10.1532/lh96.04049 · Cited by 124
Treatment of rheumatoid arthritis: Unraveling the conundrum
Zampeli, E., Vlachoyiannopoulos, P. G., & Tzioufas, A. G. (2015) · Journal of Autoimmunity · doi:10.1016/j.jaut.2015.10.003 · Cited by 126
Manipulation of the hepcidin pathway for therapeutic purposes
Fung, E., & Nemeth, E. (2013) · Haematologica · doi:10.3324/haematol.2013.084624 · Cited by 126
Self-citationThe role of IL-6 and IL-6 blockade in COVID-19
Potere, N., Batticciotto, A., Vecchié, A., Porreca, E., Cappelli, A., Abbate, A., Dentali, F., & Bonaventura, A. (2021) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2021.1919086 · Cited by 127
Iron and innate antimicrobial immunity-depriving the pathogen, defending the host
Nairz, M., Dichtl, S., Schroll, A., Haschka, D., Tymoszuk, P., Theurl, I., & Weiss, G. (2018) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2018.03.007 · Cited by 123
Regulation of TMPRSS6 by BMP6 and iron in human cells and mice
Meynard, D., Vaja, V., Sun, C. C., Corradini, E., Chen, S., López-Otín, C., Grgurević, L., Hong, C. C., Stirnberg, M., Gütschow, M., et al. (2011) · Blood · doi:10.1182/blood-2011-04-348698 · Cited by 132
Hepcidin – central regulator of iron metabolism
Atanasiu, V., Manolescu, B. N., & Stoian, I. A.-M. (2006) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2006.00772.x · Cited by 123
“The same response was observed in an in vivo study using both mice and humans as experimental model (31).”
BackgroundIron dysregulation in Huntington's disease
Müller, M., & Leavitt, B. R. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12739 · Cited by 123
“Inflammation also induces cytokines that affect levels of hepcidin, the master regulator of iron in the body produced by liver (Krause et al. 2000; Park et al. 2001; Nemeth et al. 2004; De Domenico et al. 2010; Armitage et al. 2011).”
BackgroundRamey, G., Deschemin, J., & Vaulont, S. (2009) · Haematologica · doi:10.3324/haematol.2008.003541 · Cited by 122
Maternal serum hepcidin is low at term and independent of cord blood iron status
Rehu, M., Punnonen, K. R. A., Ostland, V. E., Heinonen, S. T., Westerman, M. E., Pulkki, K. J., & Sankilampi, U. (2010) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2010.01479.x · Cited by 122
“The mechanism behind this may be related to cytokine activation during labor (25), as inflammation and inflammatory cytokines stimulate hepcidin expression (26, 27).”
BackgroundSmolen, J. S., Schoels, M., Nishimoto, N., Breedveld, F. C., Burmester, G. R., Dougados, M., Emery, P., Ferraccioli, G., Gabay, C., Gibofsky, A., et al. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2012-202469 · Cited by 122
Membrane-Anchored Serine Proteases in Vertebrate Cell and Developmental Biology
Szabo, R., & Bugge, T. H. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154247 · Cited by 125
“Hepcidin is regulated at the level of transcription, as it is induced by iron overload and suppressed by iron deficiency, anemia, and hypoxia (Nemeth et al. 2004a, Nicolas et al. Annu Rev Cell Dev Biol.”
BackgroundTwo nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency
Guillem, F., Lawson, S., Kannengiesser, C., Westerman, M. E., Beaumont, C., & Grandchamp, B. (2008) · Blood · doi:10.1182/blood-2008-05-154740 · Cited by 121
“Second, absorption of a bolus of ferrous iron increased serum iron levels by 13 μmol/L rather than the predicted minimum of 18 μmol/L, suggesting a partial block in intestinal iron absorption (14).”
BackgroundMethodThe Anemia of Inflammation/Malignancy: Mechanisms and Management
Adamson, J. W. (2008) · Hematology · doi:10.1182/asheducation-2008.1.159 · Cited by 123
“A second well-recognized pathway that regulates hepcidin gene expression is the IL-6–mediated inflammatory signaling pathway.(36,37) IL-6 directly upregulates hepcidin gene expression.”
Astrocyte hepcidin is a key factor in LPS-induced neuronal apoptosis
You, L., Yan, C.-Z., Zheng, B.-J., Ci, Y., Chang, S., Yu, P., Gao, G., Li, H., Dong, T., & Chang, Y. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.93 · Cited by 123
Taniguchi, R., Kato, H. E., Font, J., Deshpande, C. N., Wada, M., Ito, K., Ishitani, R., Jormakka, M., & Nureki, O. (2015) · Nature Communications · doi:10.1038/ncomms9545 · Cited by 120
Bacterial Transition Metal P1B-ATPases: Transport Mechanism and Roles in Virulence
ARGÜELLO, J. M., González‐Guerrero, M., & Raimunda, D. (2011) · Biochemistry · doi:10.1021/bi201418k · Cited by 125
“Upon release of the cytokine interleukin 6, the hormone hepcidin is produced inhibiting iron release from the enterocyte and causing a generalized drop of iron levels in the blood (68).”
BackgroundSMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression
Mleczko‐Sanecka, K., Casanovas, G., Ragab, A., Breitkopf, K., Müller, A., Boutros, M., Dooley, S., Hentze, M. W., & Muckenthaler, M. U. (2009) · Blood · doi:10.1182/blood-2009-09-238105 · Cited by 124
Aronson, D., Suleiman, M., Agmon, Y., Suleiman, A., Blich, M., Kapeliovich, M. R., Beyar, R., Markiewicz, W., & Hammerman, H. (2007) · European Heart Journal · doi:10.1093/eurheartj/ehm013 · Cited by 120
“The infarction-related inflammatory state with excess cytokine production may suppress erythropoiesis(19,20) and impair intestinal iron absorption.(21) Use of angiotensin converting-enzyme inhibitors may contribute to anaemia by inhibiting erythropoiesis.”
BackgroundMolecular evolution and characterization of hepcidin gene products in vertebrates
Hilton, K. B., & Lambert, L. A. (2008) · Gene · doi:10.1016/j.gene.2008.02.016 · Cited by 122
Iron-Refractory Iron Deficiency Anemia
Finberg, K. E. (2009) · Seminars in Hematology · doi:10.1053/j.seminhematol.2009.06.006 · Cited by 119
Benefits and Risks of Iron Supplementation in Anemic Neonatal Pigs
Lipiński, P., Starzyński, R. R., Canonne‐Hergaux, F., Tudek, B., Oliński, R., Kowalczyk, P., Dziaman, T., Thibaudeau, O., Gralak, M. A., Smuda, E., et al. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.091020 · Cited by 119
“It is known that the birth process initiates an acute phase response in the healthy fetus-newborn infant with increased circulating levels of interleukin-6,(35) a wellknown inflammatory cytokine that is responsible for the induction of Hepc during inflammation.(36) Surprisingly, in contrast to anemic piglets, the Hepc…”
BackgroundDysregulated iron metabolism in polycythemia vera: etiology and consequences
Ginzburg, Y. Z., Feola, M., Zimran, E., Várkonyi, J., Ganz, T., & Hoffman, R. (2018) · Leukemia · doi:10.1038/s41375-018-0207-9 · Cited by 118
“Hepcidin transcription is increased by iron loading [65] and by elevated levels of inflammatory cytokines [72] but is suppressed by tissue hypoxia [73], iron deficiency, and ineffective erythropoiesis.”
BackgroundSelf-citationRatledge, C. (2007) · Food and Nutrition Bulletin · doi:10.1177/15648265070284s405 · Cited by 121
Iron deficiency syndromes and iron‐restricted erythropoiesis (CME)
Goodnough, L. T. (2011) · Transfusion · doi:10.1111/j.1537-2995.2011.03495.x · Cited by 121
“The increase appears to be mediated by interleukin-6/STAT3, as well as other cytokine pathways.(55) Because of this, hepcidin levels are elevated in a range of inflammatory diseases including rheumatologic diseases, inflammatory bowel disease, infections, critical illness, and malignancies.”
BackgroundIron Homeostasis in Healthy Kidney and its Role in Acute Kidney Injury
Scindia, Y. M., Leeds, J. T., & Swaminathan, S. (2018) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2018.10.006 · Cited by 120
Molecular pathogenesis of anemia of chronic disease
Ganz, T. (2005) · Pediatric Blood & Cancer · doi:10.1002/pbc.20656 · Cited by 119
“In summary, it now appears that the IL-6—hepcidin axis is responsible for the induction of hypoferremia during inflammation.”
BackgroundInfluentialSelf-citationInhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia
Agoro, R., Montagna, A., Goetz, R. M., Aligbe, O., Singh, G. K., Coe, L. M., Mohammadi, M., Rivella, S., & Sitara, D. (2018) · The FASEB Journal · doi:10.1096/fj.201700667r · Cited by 117
Regulation of hepcidin: Insights from biochemical analyses on human serum samples
Kemna, E., Kartikasari, A. E. R., van Tits, L. J. H., Pickkers, P., Tjalsma, H., & Swinkels, D. W. (2007) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2007.10.002 · Cited by 117
“Elevated iron stores, marked by increased iron saturation of transferrin, are predicted to induce hepcidin production in order to decrease iron absorption and demonstrated as such in healthy volunteers treated with oral iron [ 25 ].”
BackgroundThe gut in iron homeostasis: role of HIF-2 under normal and pathological conditions
Mastrogiannaki, M., Matak, P., & Peyssonnaux, C. (2013) · Blood · doi:10.1182/blood-2012-11-427765 · Cited by 116
Iron: An Essential Element of Cancer Metabolism
Hsu, M. Y., Mina, E., Roetto, A., & Porporato, P. E. (2020) · Cells · doi:10.3390/cells9122591 · Cited by 119
Clinical value of blocking IL-6 receptor
Mima, T., & Nishimoto, N. (2009) · Current Opinion in Rheumatology · doi:10.1097/bor.0b013e3283295fec · Cited by 115
Peters, H. P. E., Laarakkers, C. M., Swinkels, D. W., & Wetzels, J. F. M. (2009) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfp546 · Cited by 115
Hepcidin in human iron disorders: Therapeutic implications
Pietrangelo, A. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.08.004 · Cited by 115
“A key player in hepcidin activation during inflammation is interleukin 6 (IL-6) [27], which activates hepcidin transcription through STAT3 [28–30], although an intact BMP-SMAD signaling pathway seems to be also required for such activity [31–34].”
BackgroundHepcidin modulation in human diseases: From research to clinic
Piperno, A., Mariani, R., Trombini, P., & Girelli, D. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.538 · Cited by 117
Vuillermot, S., Luan, W., Meyer, U., & Eyles, D. W. (2017) · Molecular Autism · doi:10.1186/s13229-017-0125-0 · Cited by 116
“availability of these elements which are essential for the invading pathogens [65, 66].”
BackgroundKatsarou, A., & Pantopoulos, K. (2018) · Pharmaceuticals · doi:10.3390/ph11040127 · Cited by 115
“IL-6 is critical for inflammatory induction of hepcidin, and Il6-/- (IL-6 knockout) mice exhibit an impaired hypoferremic response to acute inflammation [122].”
BackgroundSingh, V., Yeoh, B. S., Xiao, X., Kumar, M., Bachman, M. A., Borregaard, N., Joe, B., & Vijay–Kumar, M. (2015) · Nature Communications · doi:10.1038/ncomms8113 · Cited by 119
Why cells need iron: a compendium of iron utilisation
Teh, M. R., Armitage, A. E., & Drakesmith, H. (2024) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2024.04.015 · Cited by 114
Cercamondi, C. I., Egli, I. M., Ahouandjinou, E., Dossa, R. A. M., Zeder, C., Salami, L., Tjalsma, H., Wiegerinck, E. T. G., Tanno, T., Hurrell, R. F., et al. (2010) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2010.30051 · Cited by 114
“High circulating hepcidin can reduce iron absorption from the gut and increase iron sequestration in the reticuloendothelial system (RES) (14) by blocking the iron-transporter ferroportin; the resulting hypoferremia limits the iron available for erythropoiesis and contributes to anemia (15, 16).”
BackgroundLi, Y., Pan, K., Chen, L. V., Ning, J.-L., Li, X., Yang, T., Terrando, N., Gu, J., & Tao, G. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0740-2 · Cited by 116
“During chronic inflammation, higher levels of hepcidin and IL-6 have been related to anemia of inflammation, a condition that prevents release of iron from intracellular store [35].”
Young, B. Y., & Zaritsky, J. J. (2009) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.02190309 · Cited by 114
“In the case of inflammation, the primary mediator seems to be increased IL-6 levels, which in turn cause the binding of Signal Transducer and Activator of Transcription 3 to the hepcidin promoter, increasing its activity (8,10).”
BackgroundTumour necrosis factor α causes hypoferraemia and reduced intestinal iron absorption in mice
Laftah, A. H., Sharma, N., Brookes, M., McKie, A. T., Simpson, R. J., Iqbal, T. H., & Tselepis, C. (2006) · Biochemical Journal · doi:10.1042/bj20060215 · Cited by 114
A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates
Cooke, K. S., Hinkle, B., Salimi-Moosavi, H., Foltz, I., King, C., Rathanaswami, P., Winters, A., Steavenson, S., Begley, C. G., Molineux, G., et al. (2013) · Blood · doi:10.1182/blood-2013-06-505792 · Cited by 113
“Hepcidin is homeostatically regulated to maintain serum iron within defined limits(6-8) but can also be induced by inflammation.(9,10) Anemia is observed in several patient populations that exhibit inflammation, such as patients with severe trauma, chronic kidney disease (CKD), and cancer.”
BackgroundRegulation of Type II Transmembrane Serine Proteinase TMPRSS6 by Hypoxia-inducible Factors
Lakhal‐Littleton, S., Schödel, J., Townsend, A., Pugh, C. W., Ratcliffe, P. J., & Mole, D. R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.173096 · Cited by 119
Interleukin-6 and rheumatic diseases.
Lipsky, P. E. (2006) · Arthritis Research & Therapy · doi:10.1186/ar1918 · Cited by 113
“This was also observed in RA and sJIA patients treated with tocilizumab [27,28].”
ResultKell, D. B., & Pretorius, E. (2018) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12407 · Cited by 117
“The inflammatory cytokine interleukin-6 (IL-6) also induces hepcidin production (Chesney et al., 2015; Ganz & Nemeth, 2015; Lee et al., 2005; Nemeth et al., 2004).”
BackgroundKanbay, M., Perazella, M. A., Kasapoğlu, B., Köroğlu, M., & Covic, A. C. (2009) · Blood Purification · doi:10.1159/000245041 · Cited by 114
Iron, glucose and fat metabolism and obesity: an intertwined relationship
Hilton, C., Sabaratnam, R., Drakesmith, H., & Karpe, F. (2023) · International Journal of Obesity · doi:10.1038/s41366-023-01299-0 · Cited by 113
“The inflammatory cytokine interleukin (IL)-6 induces hepcidin [15] through the phosphorylation of”
Background
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.
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