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 Regulation of Iron Transport
Collins, J. F., Wessling‐Resnick, M., & Knutson, M. D. (2008) · Journal of Nutrition · doi:10.3945/jn.108.096347 · Cited by 201
“(10) have shown that the cytokine interleukin (IL)-6 is necessary and sufficient for induction of hepcidin during inflammation, establishing that the iron regulatory peptide plays a key role in the anemia of chronic diseases.”
BackgroundMethodInfluentialdel Giudice, E. M., Santoro, N., Amato, A., Brienza, C., Calabrò, P., Wiegerinck, E. T. G., Cirillo, G., Tartaglione, N., Grandone, A., Swinkels, D. W., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1361 · Cited by 201
“On the other hand, chronic hyperstimulation of hepcidin during inflammatory states, mainly mediated by the cytokine IL-6, is the leading factor producing the socalled anemia of inflammation or anemia of chronic disease, which has features of ironrestricted erythropoiesis (20, 21).”
BackgroundDe Domenico, I., Zhang, T. Y., Koening, C. L., Branch, R. W., London, N., Lo, E., Daynes, R. A., Kushner, J. P., Li, D., Ward, D. M., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42011 · Cited by 197
Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia
Rivera, S., Liu, L., Nemeth, E., Gabayan, V., Sorensen, O. E., & Ganz, T. (2005) · Blood · doi:10.1182/blood-2004-08-3375 · Cited by 196
Self-citationAntimicrobial Mechanisms of Macrophages and the Immune Evasion Strategies of Staphylococcus aureus
Flannagan, R. S., Heit, B., & Heinrichs, D. E. (2015) · Pathogens · doi:10.3390/pathogens4040826 · Cited by 211
“secreted from the liver, binds to surface expressed Fpn to induce its endocytosis, and subsequent degradation, thereby preventing Fe export [131,133,134].”
BackgroundCorradini, E., Meynard, D., Wu, Q., Chen, S., Ventura, P., Pietrangelo, A., & Babitt, J. L. (2011) · Hepatology · doi:10.1002/hep.24359 · Cited by 194
Modern iron replacement therapy: clinical and pathophysiological insights
Girelli, D., Ugolini, S., Busti, F., Marchi, G., & Castagna, A. (2017) · International Journal of Hematology · doi:10.1007/s12185-017-2373-3 · Cited by 196
“In acute inflammatory conditions hepcidin release from hepatocytes increases rapidly (within few hours) and exponentially (by more than 10–40-folds) [36, 37].”
BackgroundThe Role of Iron in the Immune Response to Bacterial Infection
Cherayil, B. J. (2011) · Immunologic Research · doi:10.1007/s12026-010-8199-1 · Cited by 191
Iron Balance and the Role of Hepcidin in Chronic Kidney Disease
Ganz, T., & Nemeth, E. (2016) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2016.02.001 · Cited by 195
“Inflammation induces hepcidin transcriptionally, mainly through interleukin-6, 14 its receptor, and the Jak2-Stat3 pathway, but a second inflammatory pathway recently was identified, stimulating hepcidin through activin B, the BMP receptor, and its Smad signaling mechanism.”
Self-citationThe Impact of Dietary Transition Metals on Host-Bacterial Interactions
Lopez, C. A., & Skaar, E. P. (2018) · Cell Host & Microbe · doi:10.1016/j.chom.2018.05.008 · Cited by 190
“baumannii infection triggers the release of calprotectin from infiltrating neutrophils to limit metal availability to extracellular bacteria while host metal transporters, including NRAMP1 (Nevo and Nelson, 2006), export multiple divalent metals out of bacteria-containing endosomes.”
InfluentialPharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats
Theurl, I., Schroll, A., Sonnweber, T., Nairz, M., Theurl, M., Willenbacher, W., Eller, K., Wolf, D., Seifert, M., Sun, C. C., et al. (2011) · Blood · doi:10.1182/blood-2011-03-345066 · Cited by 189
Détivaud, L., Nemeth, E., Boudjéma, K., Turlin, B., Troadec, M., Leroyer, P., Ropert, M., Jacquelinet, S., Courselaud, B., Ganz, T., et al. (2005) · Blood · doi:10.1182/blood-2004-12-4855 · Cited by 191
Self-citationOn risks and benefits of iron supplementation recommendations for iron intake revisited
Schümann, K., Ettle, T., Szegner, B., Elsenhans, B., & Solomons, N. W. (2007) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2007.06.002 · Cited by 191
Iron homeostasis: An anthropocentric perspective
Coffey, R., & Ganz, T. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.781823 · Cited by 194
“As a side effect, the IL-6driven increase in hepcidin and the corresponding decrease in iron availability for erythropoiesis are the major causes of the anemia of inflammation (56 –58), in which iron-restricted anemia develops because of impaired mobilization of iron from stores.”
BackgroundInfluentialSelf-citationIron in immune cell function and host defense
Haschka, D., Hoffmann, A., & Weiss, G. (2021) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2020.12.005 · Cited by 188
Theurl, I., Mattle, V., Seifert, M., Mariani, M., Marth, C., & Weiss, G. (2006) · Blood · doi:10.1182/blood-2005-08-3364 · Cited by 188
Hypoxia-inducible factors link iron homeostasis and erythropoiesis
Shah, Y. M., & Xie, L. (2014) · Gastroenterology · doi:10.1053/j.gastro.2013.12.031 · Cited by 187
Siderophore-mediated iron acquisition and modulation of host-bacterial interactions
Ellermann, M., & Arthur, J. C. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.10.489 · Cited by 186
Leptin Increases the Expression of the Iron Regulatory Hormone Hepcidin in HuH7 Human Hepatoma Cells
Chung, B., Matak, P., McKie, A. T., & Sharp, P. (2007) · Journal of Nutrition · doi:10.1093/jn/137.11.2366 · Cited by 188
Towards an Immunophenotype of Schizophrenia: Progress, Potential Mechanisms, and Future Directions
Miller, B. J., & Goldsmith, D. R. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.211 · Cited by 182
Iron refractory iron deficiency anemia
Falco, L. D., Sánchez, M., Silvestri, L., Kannengiesser, C., Muckenthaler, M. U., Iolascon, A., Gouya, L., Camaschella, C., & Beaumont, C. (2013) · Haematologica · doi:10.3324/haematol.2012.075515 · Cited by 199
Sun, C. C., Vaja, V., Babitt, J. L., & Lin, H. Y.-F. (2011) · American Journal of Hematology · doi:10.1002/ajh.23110 · Cited by 185
“Long-term hepcidin production, due to its ability to inhibit ferroportin function on duodenal enterocytes and macrophages, leads to poor iron absorption from the gut and increased iron retention that is a hallmark of ACD [7,52].”
BackgroundSemrin, G., Fishman, D. S., Bousvaros, A., Zholudev, A., Saunders, A. C., Correia, C. E., Nemeth, E., Grand, R. J., & Weinstein, D. A. (2006) · Inflammatory Bowel Diseases · doi:10.1097/01.mib.0000235097.86360.04 · Cited by 181
Self-citationMechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure
van der Putten, K., Braam, B. G., Jie, K. E., & Gaillard, S. (2007) · Nature Reviews Nephrology · doi:10.1038/ncpneph0655 · Cited by 182
“Hepcidin is a type II acute-phase protein produced in the liver that has been proposed to be the central regulator of iron metabolism ( Figure 3 )”
BackgroundRegulation of Iron Metabolism by Hepcidin under Conditions of Inflammation
Schmidt, P. J. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.650150 · Cited by 188
“More recently, ALK3, the primary type I receptor BMP receptor involved in hepcidin regulation, was shown to be crucial for IL-6-mediated hepcidin induction (51).”
BackgroundInfluentialGraham, R. M. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i35.4725 · Cited by 184
Besson-Fournier, C., Latour, C., Kautz, L., Bertrand, J., Ganz, T., Roth, M.-P., & Coppin, H. (2012) · Blood · doi:10.1182/blood-2012-02-411470 · Cited by 179
Self-citationSantana-Codina, N., del Rey, M. Q., Kapner, K. S., Zhang, H., Gikandi, A., Malcolm, C., Poupault, C. L., Kuljanin, M., John, K. M., Biancur, D. E., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0043 · Cited by 182
“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels
Nairz, M., Theurl, I., Swirski, F. K., & Weiss, G. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-1944-8 · Cited by 178
“Since Bmp6 stimulates both hepcidin production by hepatocytes [6] and transcriptionally regulates macrophage effector functions [123], it may broadly orchestrate the interplay between various liver-resident cell types.”
BackgroundInfluentialHepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation
Roy, C. N., Mak, H. H., Akpan, I., Losyev, G., Zurakowski, D., & Andrews, N. C. (2007) · Blood · doi:10.1182/blood-2006-10-051755 · Cited by 178
Bao, B., Peatman, E., Li, P., He, C., & Liu, Z. (2005) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2005.03.006 · Cited by 178
“Hepcidin expression is now understood to increase with the body’s iron levels [6] and to be induced by inflammatory cytokine IL-6 during infection and inflammation [9].”
BackgroundThe liver: conductor of systemic iron balance
Meynard, D., Babitt, J. L., & Lin, H. Y.-F. (2013) · Blood · doi:10.1182/blood-2013-06-427757 · Cited by 181
“Inflammation caused by infection, autoimmune disease, or cancers stimulates the synthesis of many proinflammatory cytokines, such as interferon-g, interleukin-1, and interleukin-6 (IL-6), leading to a stimulation of hepcidin expression by the liver as well as white blood cells (Figure 3).(88,89) This induction of hepc…”
BackgroundSonnweber, T., Boehm, A., Sahanic, S., Pizzini, A., Aichner, M., Sonnweber, B., Kurz, K., Koppelstätter, S., Haschka, D., Petzer, V., et al. (2020) · Respiratory Research · doi:10.1186/s12931-020-01546-2 · Cited by 177
“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].”
BackgroundRegulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages
Liu, X.-B., Nguyen, N.-B., Marquess, K. D., Yang, F., & Haile, D. J. (2005) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2005.04.006 · Cited by 186
Cell iron status influences macrophage polarization
Agoro, R., Taleb, M., Quesniaux, V. F. J., & Mura, C. (2018) · PLoS ONE · doi:10.1371/journal.pone.0196921 · Cited by 182
A Novel TLR4-Mediated Signaling Pathway Leading to IL-6 Responses in Human Bladder Epithelial Cells
Song, J., Duncan, M. J., Li, G., Chan, C. S. C., Grady, R. W., Stapleton, A. E., & Abraham, S. N. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030060 · Cited by 176
“These cells possess IL-6 receptors [54] and this cytokine, acting in autocrine fashion, may trigger various antimicrobial responses, such as production of antimicrobial peptides [55] and mucins, [56] as well as promote exfoliation of infected BECs.”
BackgroundIron in arterial plaque: A modifiable risk factor for atherosclerosis
Sullivan, J. L. (2009) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2008.06.005 · Cited by 176
“Interleukin 6 (IL-6) upregulation as seen in in fl ammatory states induces hepcidin synthesis [69].”
A Systems Biology Approach to Iron Metabolism
Chifman, J., Laubenbacher, R., & Torti, S. V. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4939-2095-2_10 · Cited by 189
“Hepcidin production is induced by the inflammatory cytokine interleukin-6 (IL-6), bacterial pathogens, and lipopolysaccharide [74].”
BackgroundThe role of vitamin D in regulating the iron-hepcidin-ferroportin axis in monocytes
Zughaier, S. M., Alvarez, J. A., Sloan, J. H., Konrad, R. J., & Tangpricha, V. (2014) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2014.01.003 · Cited by 174
“Lipopolysaccharide is a known inducer of hepcidin expression in macrophages and hepatocytes [18,19].”
BackgroundRegulation of Hepcidin and Iron-Overload Disease
Lee, P. L., & Beutler, E. (2009) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092205 · Cited by 174
“In vivo studies have demonstrated that both short-term (93) and chronic administration of iron (6) result in as much as a 10-fold increase in hepcidin mRNA expression.”
BackgroundMethodResultInfluentialA novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia
Guida, C., Altamura, S., Klein, F. A., Galy, B., Boutros, M., Ulmer, A. J., Hentze, M. W., & Muckenthaler, M. U. (2015) · Blood · doi:10.1182/blood-2014-08-595256 · Cited by 173
“LPS injection into mice causes the release of proinflammatory cytokines and triggers a wellcharacterized acute phase response including induction of the hepatic iron hormone hepcidin(4-6) by interleukin-6 (IL-6).(7,8) Hepcidin binds to and causes internalization and degradation of the iron exporter ferroportin, which…”
BackgroundInhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation
Steinbicker, A. U., Sachidanandan, C., Vonner, A. J., Yusuf, R. Z., Deng, D. Y., Lai, C. S., Rauwerdink, K. M., Winn, J. C., Saez, B., Cook, C. M., et al. (2011) · Blood · doi:10.1182/blood-2010-10-313064 · Cited by 173
New insights into iron regulation and erythropoiesis
Kim, A., & Nemeth, E. (2015) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000132 · Cited by 180
Self-citationUrinary hepcidin in congenital chronic anemias
Kearney, S. L., Nemeth, E., Neufeld, E. J., Thapa, D., Ganz, T., Weinstein, D. A., & Cunningham, M. J. (2007) · Pediatric Blood & Cancer · doi:10.1002/pbc.20616 · Cited by 172
“It is upregulated by inflammation, via cytokines such as IL-6 [5].”
BackgroundMethodSelf-citationErythropoiesis: insights into pathophysiology and treatments in 2017
Zivot, A., Lipton, J. M. M., Narla, A., & Blanc, L. (2018) · Molecular Medicine · doi:10.1186/s10020-018-0011-z · Cited by 187
Costa, M. M., Maehr, T., Díaz‐Rosales, P., Secombes, C. J., & Wang, T. (2011) · Molecular Immunology · doi:10.1016/j.molimm.2011.05.027 · Cited by 171
The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity
Golonka, R. M., Yeoh, B. S., & Vijay–Kumar, M. (2019) · Journal of Innate Immunity · doi:10.1159/000494627 · Cited by 180
Iron Status and the Acute Post-Exercise Hepcidin Response in Athletes
Peeling, P., Sim, M., Badenhorst, C. E., DAWSON, B. T., Govus, A. D., Abbiss, C. R., Swinkels, D. W., & Trinder, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093002 · Cited by 171
“Increases in hepcidin levels usually occur as a homeostatic response to inflammatory stimuli (namely the inflammatory cytokine interleukin-6: IL-6) or elevated iron levels [9], ultimately reducing dietary iron absorption from the small intestine, and reducing the ability of macrophages to recycle iron from senescent e…”
BackgroundMarques, O., Weiß, G., & Muckenthaler, M. U. (2022) · Blood · doi:10.1182/blood.2021013472 · Cited by 176
Iron and Immunity: Immunological Consequences of Iron Deficiency and Overload
Cherayil, B. J. (2010) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-010-0095-9 · Cited by 170
“Hepcidin binds to FPN and induces its Janus kinase 2 (Jak2)-dependent phosphorylation, internalization and lysosomal degradation, thereby decreasing cellular iron efflux from macrophages and duodenal enterocytes (De Domenico et al. 2007, 2009; Nemeth et al. 2004b).”
Hepcidin Is Involved in Iron Regulation in the Ischemic Brain
Ding, H., Yan, C.-Z., Shi, H., Zhao, Y., Chang, S., Yu, P., Wu, W., Zhao, C., Chang, Y., & Duan, X. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025324 · Cited by 172
“To understand the mechanism of upregulation of hepcidin caused by brain ischemia, we further examined the expression of STAT3 and phosphorylated STAT3 (p-STAT3) in the cerebral cortex (Fig.7A), hippocampus (Fig.7B) and corpus striatum (Fig.7C).”
BackgroundInfluentialFurutani, T., Hino, K., Okuda, M., Gondo, T., Nishina, S., Kitase, A., Korenaga, M., Xiao, S., Weinman, S. A., Lemon, S. M., et al. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.02.060 · Cited by 169
The Regulation of Cellular Iron Metabolism
Chua, A. C. G., Graham, R. M., Trinder, D., & Olynyk, J. K. (2007) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360701428257 · Cited by 172
Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children
Prentice, A. M., Doherty, C. P., Abrams, S. A., Cox, S. E., Atkinson, S. H., Verhoef, H., Armitage, A. E., & Drakesmith, H. (2012) · Blood · doi:10.1182/blood-2011-11-391219 · Cited by 167
“12,39 In this respect, the fact that hepcidin causes rapid hypoferremia in response to infection 39-41 and that it declines rapidly after an infection or inflammatory signal has been cleared 26,27 (thus allowing rapid absorption of dietary iron and remobilization of sequestered iron) would favor…”
BackgroundNramp1 promotes efficient macrophage recycling of iron following erythrophagocytosis in vivo
Soe-Lin, S., Apte, S. S., Andriopoulos, B., Andrews, M. C., Schranzhofer, M., Kahawita, T., Garcia-Santos, D., & Ponka, P. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900808106 · Cited by 167
Anemia and Iron Deficiency in Cancer Patients: Role of Iron Replacement Therapy
Busti, F., Marchi, G., Ugolini, S., Castagna, A., & Girelli, D. (2018) · Pharmaceuticals · doi:10.3390/ph11040094 · Cited by 169
“, IL-6, IL-1, TNF-α, and interferon-γ), that upregulate hepcidin synthesis in the liver [48,49].”
BackgroundZRT/IRT-like Protein 14 (ZIP14) Promotes the Cellular Assimilation of Iron from Transferrin
Zhao, N., Gao, J., Enns, C. A., & Knutson, M. D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.143248 · Cited by 166
A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy
Tanaka, T., Narazaki, M., Ogata, A., & Kishimoto, T. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.01.009 · Cited by 166
Role of Interleukin-6 in the Anemia of Chronic Disease
Raj, D. S. (2008) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2008.01.006 · Cited by 168
Lanser, L., Fuchs, D., Kurz, K., & Weiß, G. (2021) · Nutrients · doi:10.3390/nu13113732 · Cited by 179
Bridle, K. R., Cheung, T., Murphy, T. L., Walters, M. M., Anderson, G. J., Crawford, D. H., & Fletcher, L. M. (2006) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2006.00002.x · Cited by 165
Association between obesity and iron deficiency (Review)
Alshwaiyat, N. M., Ahmad, A., Hassan, W. M. R. W., & Al‐Jamal, H. A. N. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10703 · Cited by 176
“In people with overweight and obesity, serum hepcidin and serum interleukin‐6 are significantly higher than those with normal weight (12,34).”
BackgroundIron induces anti-tumor activity in tumor-associated macrophages
Costa da Silva, M., Breckwoldt, M. O., Vinchi, F., Correia, M. P., Stojanovic, A., Thielmann, C. M., Meister, M., Muley, T., Warth, A., Platten, M., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01479 · Cited by 164
“Tumor-bearing mice neither showed elevated serum levels of the inflammatory cytokines IL-6 and IL-1β, known activators of hepcidin expression (43, 44) (Figure S3B in Supplementary Material) nor increased hepatic hepcidin mRNA levels (Hamp1) (Figure S3C in Supplementary Material).”
BackgroundContribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli
Huang, H., Constante, M., Layoun, A., & Santos, M. M. (2009) · Blood · doi:10.1182/blood-2008-08-173641 · Cited by 164
Development of an ALK2-Biased BMP Type I Receptor Kinase Inhibitor
Mohedas, A. H., Xing, X., Armstrong, K. A., Bullock, A. N., Cuny, G. D., & Yu, P. B. (2013) · ACS Chemical Biology · doi:10.1021/cb300655w · Cited by 164
Elevated Systemic Hepcidin and Iron Depletion in Obese Premenopausal Females
Tussing-Humphreys, L. M., Nemeth, E., Fantuzzi, G., Freels, S. A., Guzman, G., Holterman, A. L., & Braunschweig, C. L. (2009) · Obesity · doi:10.1038/oby.2009.319 · Cited by 170
“Direct IL-6 stimulation has been shown to significantly increase hepcidin via the JAK/STAT3 signaling pathway (35,38).”
BackgroundSelf-citationRetinal Degeneration and Alzheimer’s Disease: An Evolving Link
Ashok, A., Singh, N., Chaudhary, S., Bellamkonda, V., Kritikos, A. E., Wise, A. S., Rana, N. A., McDonald, D., & Ayyagari, R. V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197290 · Cited by 164
“The inflammatory signal supersedes the signal from iron, and is the cause of the anemia of chronic inflammation, where iron is sequestered within liver cells and additional uptake is blocked despite low-circulating iron [114].”
Hepcidins in amphibians and fishes: Antimicrobial peptides or iron-regulatory hormones?
Shi, J. N., & Camus, A. C. (2005) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2005.10.009 · Cited by 167
“In addition, although transcription of hepcidin mRNA is stimulated by iron loading in mice [10], humans [9], and rats [9,33], isolated human and murine primary hepatocytes exposed to iron do not increase transcription of the HAMP [9,30].”
BackgroundFinberg, K. E., Whittlesey, R. L., Fleming, M. D., & Andrews, N. C. (2010) · Blood · doi:10.1182/blood-2009-05-224808 · Cited by 167
Iron deficiency anemia in inflammatory bowel disease
Kaitha, S. R., Bashir, M. H., & Ali, T. (2015) · World Journal of Gastrointestinal Pathophysiology · doi:10.4291/wjgp.v6.i3.62 · Cited by 164
The anaemia of cancer: death by a thousand cuts
Spivak, J. L. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1648 · Cited by 166
The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial: Rationale, Design, and Methods
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“elevated proinflammatory cytokines trigger increased hepatic synthesis of hepcidin, which suppresses iron absorption and utilization [56, 57], leading to iron deficiency anemia [58].”
BackgroundModification of iron regulation by the inflammatory response
WEISS, G. (2005) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2004.09.001 · Cited by 161
Iron Deficiency Anemia: Focus on Infectious Diseases in Lesser Developed Countries
Shaw, J. G., & Friedman, J. F. (2011) · Anemia · doi:10.1155/2011/260380 · Cited by 161
“In response to inflammation, in particular IL-6, hepcidin is synthesized [72].”
BackgroundThe diagnosis and management of the haematologic manifestations of lupus
Velo-García, A., Castro, S. G., & Isenberg, D. A. (2016) · Journal of Autoimmunity · doi:10.1016/j.jaut.2016.07.001 · Cited by 165
Schwoebel, F., van Eijk, L. T., Zboralski, D., Sell, S., Buchner, K., Maasch, C., Purschke, W. G., Humphrey, M., Zöllner, S., Eulberg, D., et al. (2013) · Blood · doi:10.1182/blood-2012-09-456756 · Cited by 158
Icardi, A., Paoletti, E., De Nicola, L., Mazzaferro, S., Russo, R., & Cozzolino, M. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft021 · Cited by 158
Murphy, A., Witcher, D. R., Luan, P., & Wroblewski, V. J. (2007) · Blood · doi:10.1182/blood-2006-11-057471 · Cited by 158
The role of iron in host–microbiota crosstalk and its effects on systemic glucose metabolism
Mayneris‐Perxachs, J., Moreno‐Navarrete, J. M., & Fernández‐Real, J. M. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00721-3 · Cited by 161
Polizzotto, M. N., Uldrick, T. S., Wang, V., Aleman, K., Wyvill, K. M., Marshall, V., Pittaluga, S., O’Mahony, D., Whitby, D., Tosato, G., et al. (2013) · Blood · doi:10.1182/blood-2013-08-519959 · Cited by 158
“6) 100 (6-567) 3 (15) 198 (91-338) (abnormal if ,161 3 10(3) cells/mL) Leukocytes (10(3) cells/mL)‖ 11 (32.”
A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis
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“Hepcidin synthesis is transcriptionally regulated by iron through the BMP receptor complex and its Smad pathway (shades of blue) and by inflammation predominantly via the IL-6 receptor and its JAK-STAT3 pathway (green).”
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“Hepcidin is a 25 kD peptide that plays a critical role in iron homeostasis and is also induced by IL6 (Nemeth et al, 2004).”
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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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