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
Nemeth, E., Valore, E. V., Territo, M., Schiller, G., Lichtenstein, A., & Ganz, T. (2003) · Blood · doi:10.1182/blood-2002-10-3235 · Cited by 1,417
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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Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression
Gordeuk, V. R., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nouraie, M., Okhotin, D. J., Polyakova, L. A., Ammosova, T., Nekhai, S., Ganz, T., et al. (2011) · Blood · doi:10.1182/blood-2011-03-345512 · Cited by 51
Self-citationSuperinfection in malaria: Plasmodium shows its iron will
Portugal, S., Drakesmith, H., & Mota, M. M. (2011) · EMBO Reports · doi:10.1038/embor.2011.213 · Cited by 55
“This failure to suppress hepcidin allows inflammatory cytokines—possibly including interleukin-6 (de Mast et al, 2009b; Nemeth et al, 2004b)—to further increase hepcidin levels, which exacerbates dyserythropoiesis by sequestering iron in macrophages.”
BackgroundSasaki, Y., Noguchi‐Sasaki, M., Yasuno, H., Yorozu, K., & Shimonaka, Y. (2012) · International Journal of Hematology · doi:10.1007/s12185-012-1217-4 · Cited by 50
“potent inducers of hepcidin expression [28, 29].”
Iron and inflammation – the gut reaction
Verma, S., & Cherayil, B. J. (2017) · Metallomics · doi:10.1039/c6mt00282j · Cited by 51
Wang, K., Wu, J., Xu, J., Gu, S., Li, Q., Cao, P., Li, M., Zhang, Y., & Zeng, F. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00803 · Cited by 51
Pathophysiology of Anemia in Heart Failure
Anand, I. S. (2010) · Heart Failure Clinics · doi:10.1016/j.hfc.2010.03.002 · Cited by 50
Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes
Gomes, A. C., Moreira, A. C., Mesquita, G., & Gomes, M. S. (2018) · Pharmaceuticals · doi:10.3390/ph11030084 · Cited by 52
“Hepcidin expression and release follow the pattern of acute phase proteins, being induced by pro-inflammatory cytokines, namely IL-6 [30,31].”
BackgroundAnimal models with enhanced erythropoiesis and iron absorption
Latunde-Dada, G. O., McKie, A. T., & Simpson, R. J. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2005.12.007 · Cited by 50
Shanmugam, N. K. N., Trebicka, E., Fu, L.-L., Shi, H. N., & Cherayil, B. J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400278 · Cited by 49
Function of the hemochromatosis protein HFE: Lessons from animal models
Pantopoulos, K. (2008) · World Journal of Gastroenterology · doi:10.3748/wjg.14.6893 · Cited by 49
Ryan, J. D., Altamura, S., Devitt, E. J., Mullins, S., Lawless, M. W., Muckenthaler, M. U., & Crowe, J. (2012) · Hepatology · doi:10.1002/hep.25666 · Cited by 49
“The inflammatory induction of hepcidin is chiefly mediated by interleukin 6 (IL-6), whereas other cytokines have also been implicated.(22,23) To investigate the stimulus for hepcidin production following PEG-IFN-a/RBV, serum levels of a panel of cytokines were measured in a subgroup of 22 patients at time 0, 12, and 2…”
BackgroundResultSTAT3 signaling within hepatocytes is required for anemia of inflammation in vivo
Sakamori, R., Takehara, T., Tatsumi, T., Shigekawa, M., Hikita, H., Hiramatsu, N., Kanto, T., & Hayashi, N. (2009) · Journal of Gastroenterology · doi:10.1007/s00535-009-0159-y · Cited by 49
“Subcutaneous injection of turpentine is a classical and widely accepted model of inflammation in mice [2, 3].”
BackgroundInfluentialHepcidin expression by human monocytes in response to adhesion and pro-inflammatory cytokines
Zhang, X., & Rovin, B. H. (2010) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2010.08.005 · Cited by 49
“IL-6 was also found to induce hepcidin in monocytes/macrophages [14,15].”
BackgroundCadmium induces iron deficiency anemia through the suppression of iron transport in the duodenum
Fujiwara, Y., Lee, J.-Y., Banno, H., Imai, S., Tokumoto, M., Hasegawa, T., Seko, Y., Nagase, H., & Satoh, M. (2020) · Toxicology Letters · doi:10.1016/j.toxlet.2020.07.005 · Cited by 49
Iron Metabolism and Inflammatory Mediators in Patients with Renal Dysfunction
Matsuoka, T., Abe, M., & Kobayashi, H. H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073745 · Cited by 53
“In contrast, protein-bound low-molecular-weight compounds, due to their strong binding with abundant serum proteins like albumin, are not readily removed by current dialysis techniques, regardless of membrane pore size [86,87].”
Backgroundvan Eijk, L. T., Kroot, J. J., Tromp, M., van der Hoeven, J. G., Swinkels, D. W., & Pickkers, P. (2011) · Critical Care · doi:10.1186/cc9408 · Cited by 48
“In concordance with this dual function, its expression is modulated by systemic iron requirements and inflammatory stimuli, as it is induced by cytokines such as IL-6 [3].”
BackgroundDetection of cord blood hepcidin levels as a biomarker for early-onset neonatal sepsis
Çizmeci, M. N., Kara, S., Kanburoğlu, M. K., Simavlı, S. A., Duvan, C. İ., & Tatlı, M. M. (2014) · Medical Hypotheses · doi:10.1016/j.mehy.2013.12.017 · Cited by 48
“An increase in urinary hepcidin concentration was demonstrated 2 h after infusion of IL-6 in human subjects [12].”
BackgroundLate stage erythroid precursor production is impaired in mice with chronic inflammation
Prince, O. D., Langdon, J., Layman, A. J., Prince, I. C., Sabogal, M. A., Mak, H. H., Berger, A. E., Cheadle, C., Chrest, F. J., Yu, Q., et al. (2012) · Haematologica · doi:10.3324/haematol.2011.053397 · Cited by 48
“Increased hepcidin can be detected in the serum within 5 h of an IL-6 infusion in humans.(4) Hepcidin levels are elevated in the urine and serum of patients with acute infection,(8) multiple myeloma(9) and chronic kidney disease.”
BackgroundHepcidin assay in serum by SELDI-TOF-MS and other approaches
Castagna, A., Campostrini, N., Zaninotto, F., & Girelli, D. (2009) · Journal of Proteomics · doi:10.1016/j.jprot.2009.08.003 · Cited by 49
Low Vitamin D is Associated With Infections and Proinflammatory Cytokines During Pregnancy
Akoh, C. C., Pressman, E. K., Cooper, E., Queenan, R. A., Pillittere, J., & O'Brien, K. O. (2017) · Reproductive Sciences · doi:10.1177/1933719117715124 · Cited by 48
Ishigami, J., Grams, M. E., Naik, R. P. P., Caughey, M. C., Loehr, L. R., Uchida, S., Coresh, J., & Matsushita, K. (2018) · Journal of the American Heart Association · doi:10.1161/jaha.117.007209 · Cited by 48
Animal Models of Anemia of Inflammation
Rivera, S., & Ganz, T. (2009) · Seminars in Hematology · doi:10.1053/j.seminhematol.2009.06.003 · Cited by 49
Self-citationIron and inflammation: in vivo and post-mortem studies in Parkinson’s disease
Martín‐Bastida, A., Tilley, B. S., Bansal, S., Gentleman, S., Dexter, D. T., & Ward, R. J. (2020) · Journal of Neural Transmission · doi:10.1007/s00702-020-02271-2 · Cited by 48
“2018) increasing intracellular iron (Nemeth et al. 2004).”
Inflammation, dysregulated iron metabolism, and cardiovascular disease
Rosenblum, S. L. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1124178 · Cited by 53
Vitamin D deficiency is associated with anaemia among African Americans in a US cohort
Smith, E. M., Alvarez, J. A., Martin, G. S., Zughaier, S. M., Ziegler, T. R., & Tangpricha, V. (2015) · British Journal Of Nutrition · doi:10.1017/s0007114515000999 · Cited by 48
“The mechanism underlying this relationship involves the antimicrobial peptide hepcidin, a hormone involved in the regulation of Fe recycling in the body that is induced by pro-inflammatory cytokines including IL-6 (12–14) .”
Andriopoulos, B., Hegedüsch, S., Mangin, J., Riedel, H.-D., Hebling, U., Wang, J., Pantopoulos, K., & Mueller, S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702463200 · Cited by 48
Hepcidin demonstrates a biphasic association with anemia in acute Plasmodium falciparum malaria
Casals-Pascual, C., Huang, H., Lakhal-Littleton, S., Thezenas, M. L., Kai, O., Newton, C. R. J. C., & Roberts, D. J. (2012) · Haematologica · doi:10.3324/haematol.2012.065854 · Cited by 47
“(5) Hepcidin is up-regulated by inflammation(6, 7) and down-regulated by iron deficiency or hypoxia.”
BackgroundKanamori, Y., Murakami, M., Sugiyama, M., Hashimoto, O., Matsui, T., & Funaba, M. (2019) · Vitamins and Hormones · doi:10.1016/bs.vh.2019.01.007 · Cited by 47
Hepcidin and iron status among pregnant women in Bangladesh.
Schulze, K. J., Christian, P. S., Ruczinski, I., Ray, A. L., Nath, A., Wu, L. S. F., & Semba, R. D. (2008) · PubMed · Cited by 48
Stimulating erythropoiesis in inflammatory bowel disease associated anemia
Tsiolakidou, G. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i36.4798 · Cited by 47
Anemia and Blood Transfusions in Critically Ill Patients
Athar, M. K., Puri, N., & Gerber, D. R. (2012) · Journal of Blood Transfusion · doi:10.1155/2012/629204 · Cited by 48
“These cytokines induce excess hepcidin production, which has been shown to downregulate ferroportin, an iron export protein on the cell surface of duodenal enterocytes, macrophages, and hepatocytes [19, 20].”
BackgroundAdvances in understanding the molecular basis for the regulation of dietary iron absorption
Fleming, R. E. (2005) · Current Opinion in Gastroenterology · doi:10.1097/01.mog.0000153362.98276.db · Cited by 47
The molecular regulation of iron metabolism
Donovan, A., & Andrews, N. C. (2004) · The Hematology Journal · doi:10.1038/sj.thj.6200540 · Cited by 48
Xiao, X., Dev, S., Canali, S., Bayer, A. L., Xu, Y., Agarwal, A., Wang, C., & Babitt, J. L. (2019) · Hepatology · doi:10.1002/hep.31048 · Cited by 47
“643 produce and secrete hepcidin,(2-4) which induces ferroportin degradation(5) to prevent iron overload and limit iron availability to pathogens.”
BackgroundHashim, H. A., Foda, O., & Ghayaty, E. (2017) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2017.10.003 · Cited by 47
“Hepcidin production is suppressed by anaemia and hypoxia and is induced by iron loading and inflammation [30, 31, 34-38].”
BackgroundCzaja, A. J. (2019) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.15173 · Cited by 47
Managing the Dual Nature of Iron to Preserve Health
Silvestri, L., Pettinato, M., Furiosi, V., Volpe, L. B., Nai, A., & Pagani, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043995 · Cited by 49
“Because hepcidin is an acute-phase protein [70], in conditions of infection/inflammation, its expression is increased by proinflammatory cytokines, mainly IL6 and IL1β, through the JAK2-STAT3 pathway [71] (Figure 3D).”
BackgroundThe Impact of Morning versus Afternoon Exercise on Iron Absorption in Athletes
McCormick, R., Moretti, D., McKay, A. K. A., Laarakkers, C. M., vanSwelm, R., Trinder, D., Cox, G. R., Zimmermann, M. B., Sim, M., Goodman, C., et al. (2019) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002026 · Cited by 47
Nairz, M., Schroll, A., Haschka, D., Dichtl, S., Tymoszuk, P., Demetz, E., Moser, P., Haas, H., Fang, F. C., Theurl, I., et al. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00110 · Cited by 46
Iron-deficiency anemia in Castleman disease: implication of the interleukin 6/hepcidin pathway
Arlet, J.-B., Hermine, O., Darnige, L., Ostland, V., Westerman, M., Badoual, C., Pouchot, J., & Capron, L. (2010) · PEDIATRICS · doi:10.1542/peds.2010-1123 · Cited by 46
“Our report (1) puts forward isolated chronic overproduction of IL-6 as a new cause of iron deficiency, (2) explains iron deficiency in CD, and (3) provides new insights into the role of IL-6 and hepcidin in ACD.”
BackgroundResultHydroxamate Production as a High Affinity Iron Acquisition Mechanism in Paracoccidioides Spp
Bailão, M. G. S., Bailão, E. F. L. C., Lechner, B. E., Gauthier, G. M., Lindner, H., Bailão, A. M., Haas, H., & Soares, C. M. D. A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0105805 · Cited by 46
Furst, D. E., Chang, H., Greenberg, J. D., Ranganath, V. K., Reed, G. W., Ozturk, Z. E., & Kremer, J. M. (2009) · PubMed · Cited by 46
Proposing a Caco-2/HepG2 cell model for in vitro iron absorption studies
Scheers, N., Almgren, A., & Sandberg, A. (2014) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2014.02.013 · Cited by 51
“Hepcidin induction by IL-6 is transferrin-independent and activated by the JAK/STAT pathway [23].”
BackgroundDunham, R. A. (2008) · Comparative Immunology Microbiology and Infectious Diseases · doi:10.1016/j.cimid.2007.11.006 · Cited by 46
“When plasma iron levels decrease, it is believed that a feedback mechanism downregulates hepcidin production in the liver [66,67].”
BackgroundEllsworth, S. G., Kwok, Y., Krasna, M. J., Bangalore, M., & Suntharalingam, M. (2005) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2004.12.038 · Cited by 46
Glinz, D., Hurrell, R. F., Righetti, A. A., Zeder, C., Adiossan, L. G., Tjalsma, H., Utzinger, J., Zimmermann, M. B., N'Goran, E. K., & Wegmüller, R. (2015) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.090175 · Cited by 46
“Inflammatory cytokines, such as IL-6, induce hepcidin production in the liver (5), reducing iron efflux from enterocytes, hepatocytes, and macrophages.”
BackgroundIroning out the mechanism of anemia in celiac disease
Hershko, C., & Patz, J. (2008) · Haematologica · doi:10.3324/haematol.2008.000828 · Cited by 47
Hoofnagle, M. H., Wamhoff, B. R., & Owens, G. K. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21761 · Cited by 47
“In an elegant report in this issue of the JCI, Nemeth, Rivera, and colleagues have elucidated an important link between inflammatory cytokines and hepcidin (10).”
BackgroundMethodResultInfluentialPsychological stress induces hypoferremia through the IL-6–hepcidin axis in rats
Zhao, M., Chen, J., Wang, W., Wang, L., Ma, L., Shen, H., & Li, M. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.05.166 · Cited by 46
“Hepcidin is also regulated by inflammatory signals [9,10], for example by IL-6.”
BackgroundMicrobiota-assisted iron uptake promotes immune tolerance in the intestine
Zhu, L., Li, G., Liang, Z., Qi, T., Deng, K., Yu, J., Peng, Y., Zheng, J., Song, Y., & Chang, X. (2023) · Nature Communications · doi:10.1038/s41467-023-38444-2 · Cited by 47
“Notably, iron de fi ciencies are frequently observed in patients with in fl ammatory bowel diseases (IBDs, including Crohn ’ s disease and ulcerative colitis) 5,6 , resulting from increased bleeding into the intestinal lumen, gut microbiota dysbiosis 7 , and in fl ammatory responses 8,9 .”
The Case for an Estrogen-iron Axis in Health and Disease
Hamad, M. A., Bajbouj, K., & Taneera, J. (2019) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-0885-1677 · Cited by 47
Tuberculosis-Associated Anemia: A Narrative Review
Dasaradhan, T., Koneti, J., Kalluru, R., Gadde, S., Cherukuri, S. P., & Chikatimalla, R. (2022) · Cureus · doi:10.7759/cureus.27746 · Cited by 49
“LPS and IL-6 induce hepcidin production [27].”
Iron deficiency anemia in IBD: an overlooked comorbidity
Shah, Y., Patel, D., & Khan, N. H. (2021) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2021.1900730 · Cited by 47
The role of hepcidin and ferroportin in iron absorption.
Oates, P. S. (2007) · PubMed · doi:10.14670/hh-22.791 · Cited by 46
Darton, T. C., Blohmke, C. J., Giannoulatou, E., Waddington, C. S., Jones, C., Sturges, P., Webster, C., Drakesmith, H., Pollard, A. J., & Armitage, A. E. (2015) · PLOS Neglected Tropical Diseases · doi:10.1371/journal.pntd.0004029 · Cited by 45
“Hepcidin upregulation in the context of inflammation/infection is typically linked to signaling via the IL-6/STAT3 pathway [19,42].”
BackgroundIron Metabolism and Iron Chelation in Sickle Cell Disease
Walter, P. B., Harmatz, P., & Vichinsky, E. P. (2009) · Acta Haematologica · doi:10.1159/000243802 · Cited by 45
“thereby reducing iron absorption. Hepcidin is also raised by the inflammatory cytokine IL-6 [”
BackgroundDiurnal cycle influences peripheral and brain iron levels in mice
Unger, E. L., Earley, C. J., & Beard, J. L. (2008) · Journal of Applied Physiology · doi:10.1152/japplphysiol.91076.2008 · Cited by 45
Should we reconsider iron administration based on prevailing ferritin and hepcidin concentrations?
Nakanishi, T., Kuragano, T., Kaibe, S., Nagasawa, Y., & Hasuike, Y. (2012) · Clinical and Experimental Nephrology · doi:10.1007/s10157-012-0694-3 · Cited by 45
“The relationship between serum hepcidin and inflammatory markers is less clear in patients with CKD, although hepcidin expression was initially found to be induced by IL-6 in inflammatory conditions [48].”
BackgroundGagliardo, B., Kubat, N. J., Faye, A., Jaouen, M., Durel, B., Deschemin, J., Canonne‐Hergaux, F., Sari, M., & Vaulont, S. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.09.018 · Cited by 45
“Hepcidin synthesis in the liver is induced by iron stores and inflammation [1,8,9], and inhibited by anemia and hypoxia [9,10].”
BackgroundThe Potential Role of Iron and Copper in Pediatric Obesity and Nonalcoholic Fatty Liver Disease
Feldman, A., Aigner, E. S., Weghuber, D., & Paulmichl, K. (2015) · BioMed Research International · doi:10.1155/2015/287401 · Cited by 45
“The expression of hepcidin is stimulated by iron, hypoxia, and proinflammatory cytokines or adipokines [19], such as interleukin 6 (IL-6) and also leptin [20, 21].”
Aguilar‐Valles, A., Jung, S., Poole, S., Flores, C., & Luheshi, G. N. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.11.003 · Cited by 47
“, 2006) and other organs (Nemeth et al., 2004).”
BackgroundInfluentialBiomarkers of immune tolerance in liver transplantation
Vionnet, J., & Fueyo, A. S. (2018) · Human Immunology · doi:10.1016/j.humimm.2018.02.010 · Cited by 45
“interleukin 6 (IL-6), induce a rapid increase of hepcidin, which reduces iron export from enterocytes, hepatocytes and macrophages [66-68].”
Iron Deficiency in Pulmonary Arterial Hypertension: A Deep Dive into the Mechanisms
Quatredeniers, M., Mendes‐Ferreira, P., Santos‐Ribeiro, D., Nakhleh, M. K., Ghigna, M., Cohen‐Kaminsky, S., & Perros, F. (2021) · Cells · doi:10.3390/cells10020477 · Cited by 45
“IL-6 plays a predominant role in this process through the upregulation of hepatic hepcidin expression, which may account for the hepcidin-driven iron deficiency observed in certain autoimmune and inflammatory diseases [41].”
BackgroundEffects of plasma transfusion on hepcidin production in human congenital hypotransferrinemia
Trombini, P., Coliva, T. A., Nemeth, E., Mariani, R., Ganz, T., Biondi, A., & Piperno, A. (2007) · Haematologica · doi:10.3324/haematol.11377 · Cited by 45
“Urinary hepcidin levels were measured at the University of California (Los Angeles, USA) as previously described.(7) As usual, fasting serum iron, transferrin and transferrin saturation, serum ferritin, cell blood and reticulocyte counts were measured before transfusion.”
MethodSelf-citationShin, D.-Y., Chung, J., Joe, Y., Pae, H., Chang, K. C., Cho, G. J., Ryter, S. W., & Chung, H. (2012) · Blood · doi:10.1182/blood-2011-07-366690 · Cited by 49
Hepcidin is regulated during blood-stage malaria and plays a protective role in malaria infection
Wang, H.-Z., He, Y.-X., Yang, C.-J., Zhou, W., & Zou, C.-G. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1101436 · Cited by 44
“IL-6 is one of the most potent inflammation factors in promoting the expression of hepcidin by the activation of STAT3 in the liver (27, 28).”
BackgroundBacterial cell wall constituents induce hepcidin expression in macrophages through MyD88 signaling
Layoun, A., & Santos, M. M. (2012) · Inflammation · doi:10.1007/s10753-012-9463-4 · Cited by 44
“Therefore, we next questioned whether macrophage iron levels in our experimental model would affect the production of IL6, the major cytokine involved in hepcidin induction in hepatocytes [25].”
Solid fuel use is associated with anemia in children
Accinelli, R. A., & Leon-Abarca, J. A. (2017) · Environmental Research · doi:10.1016/j.envres.2017.06.032 · Cited by 44
“IL-6 induces expression of hepcidin by the liver (Nemeth et al., 2004).”
BackgroundRohrlich, P., Fazilleau, N., Ginhoux, F., Firat, H., Michel, F., Cochet, M., Laham-Karam, N., Roth, M. P., Pascolo, S., Nato, F., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502309102 · Cited by 44
Maggio, M. G., Vita, F. D., Fisichella, A., Lauretani, F., Ticinesi, A., Ceresini, G., Cappola, A. R., Ferrucci, L., & Ceda, G. P. (2015) · International Journal of Endocrinology · doi:10.1155/2015/292574 · Cited by 44
“It is very well documented that T exerts anti-inflammatory properties by inhibiting the proinflammatory nuclear transcription factor kappa B (NF𝜅B) [67] and the expression of the inflammatory mediator IL-6.”
BackgroundA role for tumour necrosis factor α in human small bowel iron transport
Sharma, N., Laftah, A. H., Brookes, M., Cooper, B. T., Iqbal, T. H., & Tselepis, C. (2005) · Biochemical Journal · doi:10.1042/bj20050256 · Cited by 44
Hickerson, B. T., Westover, J. B., Wang, Z., Lee, Y.-M., & Gowen, B. B. (2019) · Journal of Virology · doi:10.1128/jvi.01278-19 · Cited by 44
“However, therapeutic manipulation of tightly regulated serum and tissue iron levels, or interference of IL-6 or hepcidin production to reduce the expression of TfR1, presents significant challenges as it has yet to be reported whether such a strategy would result in the downregulation of TfR1 in vivo.”
BackgroundInfluentialSystemic and cellular consequences of macrophage control of iron metabolism
Recalcati, S., Locati, M., & Cairo, G. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2013.01.001 · Cited by 44
Nicolaou, O., Kousios, A., Hadjisavvas, A., Lauwerys, B. R., Sokratous, K., & Kyriacou, K. C. (2016) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13031 · Cited by 44
“It appears to be associated with proinflammatory cytokines such as interleukin-6 and tumour necrosis factor-a [72, 73], molecules that are known to be implicated in SLE pathogenesis [74, 75].”
BackgroundChang, J., Chen, Y.-C., Owaga, E., Palupi, K. C., Pan, W.-H., & Bai, C. (2014) · Nutrients · doi:10.3390/nu6093929 · Cited by 44
“IL-6 promotes the development of obesity-related hypoferremia by targeting the hepcidin-ferroportin-1 axis [17].”
BackgroundAnemia and iron deficiency in patients with atrial fibrillation
Hanna‐Rivero, N., Tu, S. J., Elliott, A. D., Pitman, B. M., Gallagher, C., Lau, D. H., Sanders, P., & Wong, C. X. J. (2022) · BMC Cardiovascular Disorders · doi:10.1186/s12872-022-02633-6 · Cited by 47
“Proinflammatory cytokines such as interleukin-6 mediate the production and release of hepcidin [58].”
BackgroundHepcidin and interleukin‐6 responses to endurance exercise over the menstrual cycle
Barba‐Moreno, L., Alfaro-Magallanes, V. M., de Jonge, X. J., Díaz, Á. E., Cupeiro, R., & Peinado, A. B. (2020) · European Journal of Sport Science · doi:10.1080/17461391.2020.1853816 · Cited by 44
Davenport, G. C., Ouma, C., Hittner, J. B., Were, T., Ouma, Y., Ong’echa, J. M., & Perkins, D. J. (2010) · American Journal of Hematology · doi:10.1002/ajh.21653 · Cited by 43
Chang, J., Bird, R. J., Clague, A. E., & Carter, A. (2007) · Pathology · doi:10.1080/00313020701329732 · Cited by 43
Serum Pro-hepcidin Levels in Rheumatoid Arthritis and Systemic Lupus Erythematosus
Koca, S. S., Işık, A. T., Üstündağ, B., Metin, K., & Aksoy, K. (2008) · Inflammation · doi:10.1007/s10753-008-9060-8 · Cited by 43
“Although TNF-α was reported to inhibit hepcidin expression [ 12 ], TNF-α is a pro-inflammatory cytokine, and it is known to precede to the production of many other cytokines [41].”
BackgroundResultInfluentialDo Hemochromatosis Mutations Protect Against Iron-Mediated Atherogenesis?
Sullivan, J. L. (2009) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.109.906230 · Cited by 43
“The discovery of hepcidin [42-44] and the details of its influence on iron metabolism [45-49] illuminated patterns of macrophage iron retention and led to a conceptual volte-face on the possibility of diminished atherosclerosis in homozygotes [4;6].”
BackgroundBarton, J. C., Lee, P. L., West, C., & Bottomley, S. S. (2006) · American Journal of Hematology · doi:10.1002/ajh.20714 · Cited by 43
“4-fold on average, but returned to the baseline levels by the next day, although the subjects continued taking iron supplements for two more days [42].”
BackgroundIncreased Serum Iron Levels and Infectious Complications after Liver Transplantation
Chow, J. K. L., Werner, B. G., Ruthazer, R., & Snydman, D. R. (2010) · Clinical Infectious Diseases · doi:10.1086/654802 · Cited by 43
“Hepcidin acts by decreasing iron influx into plasma from tissues engaged in iron transport and storage [51].”
BackgroundIron homeostasis during anemia of inflammation: a prospective study of patients with tuberculosis
Cercamondi, C. I., Stoffel, N. U., Moretti, D., Zöller, T., Swinkels, D. W., Zeder, C., Mhimibra, F., Hella, J., Fenner, L., & Zimmermann, M. B. (2021) · Blood · doi:10.1182/blood.2020010562 · Cited by 43
Erythropoietin regulates intestinal iron absorption in a rat model of chronic renal failure
Srai, S. K., Chung, B., Marks, J., Pourvali, K., Solanky, N., Rapisarda, C., Chaston, T. B., Hanif, R., Unwin, R. J., Debnam, E. S., et al. (2010) · Kidney International · doi:10.1038/ki.2010.217 · Cited by 44
The Macrophage Iron Signature in Health and Disease
Mertens, C., Marques, O., Horvat, N. K., Simonetti, M., Muckenthaler, M. U., & Jung, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168457 · Cited by 44
“This MΦ subpopulation activates the production and secretion of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α; interleukin (IL)-1β, IL-6, IL-12, and IL-23; and reactive oxygen (ROS) and nitrogen (Nos) species [5,6], and is capable of presenting antigens to T cells.”
BackgroundInfluentialSerum hepcidin but not prohepcidin may be an effective marker for anemia of inflammation (AI)
Sasu, B. J., Li, H., Rose, M. J., Arvedson, T. L., Doellgast, G., & Molineux, G. (2010) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2010.07.013 · Cited by 43
Paesano, R., Natalizi, T., Berlutti, F., & Valenti, P. (2012) · Pathogens and Global Health · doi:10.1179/2047773212y.0000000043 · Cited by 44
Ilbäck, N., Frisk, P., Tallkvist, J., Gadhasson, I.-L., Blomberg, J., & Friman, G. (2008) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2007.12.001 · Cited by 42
“Further, it exerts a negative effect on Fe efflux from hepatocytes and enterocytes by binding to the Fe transporter Ferroportin 1 [38].”
BackgroundBerglund, S. K., Lönnerdal, B. L., Westrup, B., & Domellöf, M. (2011) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.013938 · Cited by 42
Robinson, J. C., Graham, B. B., Rouault, T. A., & Tuder, R. M. (2014) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2014-0021tr · Cited by 42
“sufficient to induce hepcidin expression and leads to hypoferremia in animal models of inflammation (40).”
BackgroundHohlbaum, A. M., Gille, H., Trentmann, S. M., Kolodziejczyk, M., Rattenstetter, B., Laarakkers, C. M., Katzmann, G., Christian, H., Andersen, N., Allersdorfer, A., et al. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14143 · Cited by 42
“Other strategies to reduce hepcidin expression with inhibitors of the bonemorphogenetic protein-6/haemojuvelin/ mothers against decapentaplegic homologue pathway or inhibitors of the IL-6/signal transducer and activator of transcription-3 pathway have been considered as well, since hepcidin expression is controlled by…”
BackgroundMethodInfluentialConstante, M., Wang, D., Raymond, V., Bilodeau, M., & Santos, M. M. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.060437 · Cited by 42
“These two cytokines, in turn, directly modulate the expression of hepcidin in hepatocytes.(40,43,60) Consistent with our previous findings that the inflammatory pathway overrides the iron-sensing pathway for hepcidin regulation,(35) Rgmc suppression during inflammation seems to be a prerequisite for the transcriptiona…”
BackgroundAyoya, M. A., Spiekermann‐Brouwer, G. M., Stoltzfus, R. J., Nemeth, E., Habicht, J., Ganz, T., Rawat, R., Traoré, A. K., & Garza, C. (2010) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2010.29353 · Cited by 42
“Urinary hepcidin’s correlation with the other biomarkers of inflammation and with ferritin agrees with our pilot study findings (6) and is consistent with those of Nemeth et al (5) in a different setting.”
BackgroundMethodResultInfluentialSelf-citationQuantitation of hepcidin in human urine by liquid chromatography–mass spectrometry
Bansal, S. S., Halket, J. M., Bomford, A. B., Simpson, R. J., Vasavda, N., Thein, S. L., & Hider, R. C. (2008) · Analytical Biochemistry · doi:10.1016/j.ab.2008.09.045 · Cited by 42
Syed, S., Michalski, E. S., Tangpricha, V., Chesdachai, S., Kumar, A., Prince, J., Ziegler, T. R., Suchdev, P. S., & Kugathasan, S. (2017) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000001178 · Cited by 44
“Pro-inflammatory cytokines that are often elevated in IBD (17, 18), stimulate hepatic hepcidin expression, and subsequent elevations in hepcidin may have deleterious effects on iron recycling due to decreased iron absorption from the small intestine, and iron sequestration within macrophages (18, 19).”
The Postinjury Inflammatory State and the Bone Marrow Response to Anemia
Loftus, T. J., Mira, J. C., Miller, E., Kannan, K. B., Plazas, J. M., Delitto, D., Stortz, J. A., Hagen, J. E., Parvataneni, H. K., Sadasivan, K. K., et al. (2018) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201712-2536oc · Cited by 42
Unexplained Aspects of Anemia of Inflammation
Price, E. A., & Schrier, S. L. (2010) · Advances in Hematology · doi:10.1155/2010/508739 · Cited by 43
“Those with AI had higher levels of inflammatory markers, including IL-6 and TNF-α, compared to levels found in previously reported healthy subjects, supporting the diagnostic criteria.”
BackgroundInfluentialPapillard-Maréchal, S., Sznajder, M., Hurtado-Nédelec, M., Alibay, Y., Schmitt, C., Dehoux, M., Westerman, M. E., Beaumont, C., Chevallier, B., Puy, H., et al. (2012) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.025817 · Cited by 42
Age and altitude of residence determine anemia prevalence in Peruvian 6 to 35 months old children
Accinelli, R. A., & León-Abarca, J. A. (2020) · PLoS ONE · doi:10.1371/journal.pone.0226846 · Cited by 42
“Also, at a global level, anemia rates in children are associated with the frequency of solid fuel use [48] given that traditional, inefficient stoves generate indoor pollution, higher amounts of particulate matters in the alveoli, where macrophages phagocytize them initiate an inflammatory response [49,50].”
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
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