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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11 of 30 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured
- Premisecitation§ Introduction
Patients with anemia of inflammation due to inflammatory disorders or infections have markedly increased excretion of urinary hepcidin.
“patients with AI due to inflammatory disorders or infections had markedly increased excretion of urinary hepcidin”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [12] source
- Premisecitation§ Introduction
Turpentine injections decrease serum iron in mice.
“decreased serum iron”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Nicolas, 2002, J. Clin. Invest. source
- Premisecitation§ Introduction
Turpentine injections increase hepcidin mRNA in mice.
“injections of turpentine increased hepcidin mRNA”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Nicolas, 2002, J. Clin. Invest. source
- Premisecitation§ Introduction
IL-6 strongly induces hepcidin mRNA in fresh human hepatocytes.
“strong induction of hepcidin mRNA by IL-6”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [12] source
- Premisecitation§ Introduction
IL-1α and TNFα do not strongly induce hepcidin mRNA in fresh human hepatocytes.
“but not IL-1 α or TNFα”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [12] source
- Findingown data§ Results
LPS treatment increases hepcidin mRNA levels in primary human hepatocytes.
“LPS treatment increased hepcidin mRNA levels in primary human hepatocytes”
Quote in the paperSubstantial claim - Findingown data§ Figure 1
Anti-TNFα antibodies have no detectable effect on hepcidin induction in these experiments.
“Anti-TNFα Ab's had no detectable effect in either experiment”
Quote in the paperNot a substantial claim - Findingown data§ Figure 1
Hep3B hepcidin mRNA markedly increases after exposure to M-LPS.
“Hep3B hepcidin mRNA, however, markedly increased after exposure to M-LPS”
Quote in the paperSubstantial claim - Findingown data§ Figure 1
Anti-IL-6 antibodies have similar inhibitory effects when hepatocytes or Hep3B cells are treated with conditioned medium from macrophages exposed to peptidoglycan from Staphylococcus aureus.
“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”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4
In IL-6 KO mice, hepcidin mRNA increases ninefold in iron-refed mice compared with those on an iron-deficient diet.
“in IL-6 KO mice hepcidin mRNA increased ninefold”
Quote in the paperSubstantial claim - Findingown data§ Figure 4
After 24 hours, hepcidin concentrations decline toward baseline levels.
“After 24 hours, hepcidin concentrations declined toward baseline levels”
Quote in the paperNot a substantial claim - Findingown data§ Figure 1
Median hepcidin-1 expression in the liver increases 12-fold in WT mice treated with turpentine compared with PBS-treated controls.
“Median hepcidin-1 expression in the liver increased 12-fold in WT mice treated with turpentine compared with treatment with PBS”
Quote in the paperSubstantial claim - Findingown data§ Figure 1
Hep3B hepcidin mRNA markedly increases after 24-hour stimulation with 100 ng/ml IL-6.
“or after 24-hour stimulation with 100 ng/ml IL-6 (4.9-fold ± 1.4-fold, mean ± SD, n = 5 experiments)”
Quote in the paperSubstantial claim - Findingown data§ Figure 1
Median hepcidin-1 expression in the liver decreases below baseline in turpentine-treated IL-6 KO mice.
“but decreased below baseline in turpentine-treated IL-6 KO mice”
Quote in the paperSubstantial claim - Findingown data§ Figure 1
Median serum iron is slightly higher in turpentine-treated IL-6 KO mice compared with PBS-treated mice.
“median serum iron was slightly higher in turpentine-treated IL-6 KO mice compared with PBS-treated mice”
Quote in the paperSubstantial claim - Findingown data§ Figure 4
In humans, hepcidin excretion returns to baseline levels by the next day even though subjects continued taking iron supplements for 2 more days.
“By the next day, however, hepcidin excretion returned to the baseline levels, even though the subjects continued taking iron supplements for 2 more days”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4
In humans, within 24 hours after the first dose of 65 mg iron, hepcidin excretion increases 5.4-fold on average.
“Within 24 hours after the first dose of iron, hepcidin excretion increased 5.4-fold on average”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4
IL-1α does not have a significant effect on hepcidin mRNA in Hep3B cells.
“IL-1 α did not have a significant effect in this system”
Quote in the paperNot a substantial claim - Findingown data§ Results
Human hepatoma Hep3B cells are poorly responsive to direct stimulation even by 500 ng/ml LPS.
“human hepatoma Hep3B cells were poorly responsive to direct stimulation even by 500 ng/ml LPS”
Quote in the paperSubstantial claim - Findingown data§ Figure 4
There is no significant difference between WT and KO mice in the hepcidin response to iron refeeding.
“There was no significant difference between WT and KO mice in the hepcidin response to iron refeeding”
Quote in the paperSubstantial claim - Findingown data§ Figure 1
Serum iron levels are 49% lower in turpentine-treated WT mice than in PBS-treated mice.
“Serum iron levels were 49% lower in turpentine-treated WT mice than in PBS-treated mice”
Quote in the paperSubstantial claim - Findingreasoning§ Discussion
In humans, the stimulatory effect of dietary iron on hepcidin is largely lost after the first dose of iron.
“in humans the stimulatory effect of dietary iron on hepcidin is largely lost after the first dose of iron”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4
In WT mice, median hepcidin mRNA increases 10.7-fold in iron-refed mice compared with those on an iron-deficient diet.
“in WT mice median hepcidin mRNA increased 10.7-fold in iron-refed mice compared with those on an iron-deficient diet”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4
IL-6 infusion causes a decrease in serum iron and transferrin saturation in humans.
“IL-6 infusion also caused a decrease in serum iron and transferrin saturation”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
In mice, ablation of hepcidin expression results in iron overload resembling human hemochromatosis, with iron excess in most tissues except the macrophage-rich spleen.
“ablation of hepcidin expression removed the inhibition and resulted in iron overload resembling human hemochromatosis, with iron excess in most tissues except the macrophage-rich spleen”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] source
- Interpretationown data§ Discussion
Regulation of hepcidin mRNA by iron does not require IL-6.
“regulation of hepcidin mRNA by iron does not require IL-6 since iron refeeding increased hepcidin mRNA expression in IL-6 KO mice nearly as much as in WT mice”
Quote in the paperSubstantial claim - Interpretationcitation§ Discussion
The rapid IL-6-induced decrease in transferrin saturation argues strongly against hemodilution as the cause of IL-6-mediated hypoferremia.
“The rapid IL-6-induced decrease in transferrin saturation argues strongly against hemodilution (33) as the cause of IL-6-mediated hypoferremia”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Nieken, 1995, Blood. source
- Interpretationreasoning§ Discussion
IL-6-stimulated increase in plasma hepcidin concentration blocks the release of iron from macrophages that recycle iron from senescent erythrocytes.
“IL-6-stimulated increase in plasma hepcidin concentration blocks the release of iron from macrophages that recycle iron from senescent erythrocytes”
Quote in the paperSubstantial claim - Interpretationown data§ IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin
The IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.
“the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation”
Quote in the paperSubstantial claim - Interpretationown data§ IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin
IL-6 is necessary for the induction of hepcidin during inflammation.
“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”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Hepcidin inhibits placental iron transport.
“placental iron transport”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] source
- Interpretationown data§ IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin
IL-6 is sufficient to induce hepcidin during inflammation.
“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”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Hepcidin inhibits release of recycled iron from macrophages.
“release of recycled iron from macrophages”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] source
- Premisecitation§ Figure 1
Primary hepatocytes produce IL-6 in response to LPS stimulation.
“Primary hepatocytes were previously shown to produce IL-6 in response to LPS stimulation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] source
- Interpretationown data§ Discussion
IL-6 is the main mediator of hepcidin increase in inflammation.
“IL-6 is the main mediator of hepcidin increase in inflammation”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 10
- May combine two claims. 17
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionHepcidin synthesis is regulated by dietary iron and iron stores, as well as by tissue oxygenation.
“hepcidin synthesis is regulated by dietary iron and iron stores, as well as by tissue oxygenation”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [3] source
- cites [7] source
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)
Experimental — accuracy not yet measured - cites [8] Nicolas, 2002, J. Clin. Invest. source
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)
Experimental — accuracy not yet measured
May combine two claims.
Premisecitation§ IntroductionTurpentine-induced hypoferremia is not observed in hepcidin-deficient mice, demonstrating that hepcidin is required for iron sequestration during inflammatory conditions.
“the turpentine-induced hypoferremia was not observed in hepcidin-deficient mice (8), demonstrating that hepcidin is required for iron sequestration during inflammatory conditions”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Nicolas, 2002, J. Clin. Invest. source
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)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionHepcidin mRNA expression is increased in mice with diet-induced or genetically induced iron overload.
“hepcidin mRNA expression was increased in mice with dietinduced or genetically induced iron overload”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [3] source
- cites [7] source
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)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionHepcidin mRNA expression is decreased in mice with anemia caused by bleeding or hemolysis or in mice with hypoxemia due to decreased ambient oxygen.
“decreased in mice with anemia caused by bleeding or hemolysis or in mice with hypoxemia due to decreased ambient oxygen”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [8] Nicolas, 2002, J. Clin. Invest. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionHepcidin production is diminished in the most common form of hemochromatosis caused by mutations in the HFE gene.
“in the most common form of hemochromatosis, that caused by mutations in the HFE gene”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [11] source
- cites [12] source
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)
Experimental — accuracy not yet measured
May combine two claims.
Findingown data§ Figure 4IL-6 infusion rapidly increases hepcidin excretion in humans; within 2 hours after infusion, urinary hepcidin levels are 7.5-fold higher on average than at 0 hours.
“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”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 4Two hours after IL-6 infusion, serum iron decreases on average 34% and transferrin saturation decreases 33% compared with preinfusion values.
“serum iron decreased on average 34% and transferrin saturation decreased 33% in comparison to preinfusion values”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 4TNFα markedly suppresses hepcidin mRNA levels in Hep3B cells by a mechanism that does not involve IL-6 regulation.
“TNFα markedly suppressed hepcidin mRNA levels by a mechanism that did not involve IL-6 regulation”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 1Both the effects of LPS on primary human hepatocytes and the effects of M-LPS on Hep3B cells are completely reversed when IL-6-neutralizing antibodies are added.
“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”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 1Median haptoglobin mRNA is 9.3-fold higher in turpentine-treated WT mice but only 1.9-fold higher in IL-6 KO mice.
“median haptoglobin mRNA was 9.3-fold higher in turpentine-treated WT mice but only 1.9-fold higher in IL-6 KO mice”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ DiscussionThe inflammatory and iron pathways of hepcidin stimulation respond rapidly, with major hepcidin increase detectable within 1 day in both humans and mice.
“The inflammatory and iron pathways of hepcidin stimulation respond rapidly, with major hepcidin increase detectable within 1 day in both humans and mice”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ IntroductionHepcidin mRNA is increased in the livers of LPS-treated mice and in LPS-treated hepatocytes.
“hepcidin mRNA was increased in the livers of LPS-treated mice and in LPS-treated hepatocytes”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionThere 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.
“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”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] source
May combine two claims.
Premisecitation§ IntroductionIn transgenic mice overexpressing hepcidin-1, transplacental and intestinal iron transport is blocked, and the mice die at birth from severe iron deficiency unless given parenteral iron supplementation.
“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”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] source
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ IntroductionHuman hepcidin is the functional equivalent of hepcidin-1 in mice.
“These observations suggest that human hepcidin is the functional equivalent of hepcidin-1 in mice.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionOverexpression of hepcidin-2 has no effect on iron metabolism in mice.
“Overexpression of the other known murine hepcidin gene, hepcidin-2, had no effect on iron metabolism in mice”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionHepcidin production is diminished in juvenile hemochromatosis due to mutations in the hemojuvelin gene.
“Hepcidin production was also diminished in another form of juvenile hemochromatosis due to mutations in the hemojuvelin gene”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Figure 4Hepatic hepcidin mRNA levels in mice increase in response to increased dietary iron.
“Hepatic hepcidin mRNA levels in mice were shown to increase in response to increased dietary iron”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Interpretationreasoning§ DiscussionIn IL-6 KO mice, hepcidin mRNA is suppressed, likely due to negative regulation of hepcidin synthesis by other acute-phase cytokines.
“In IL-6 KO mice, however, hepcidin mRNA was suppressed, likely due to the negative regulation of hepcidin synthesis by other acute-phase cytokines”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown data§ DiscussionChanges in serum iron concentrations reflect 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.
“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”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ Figure 6Decrease in iron supply becomes a bottleneck for hemoglobin synthesis and eventually results in anemia.
“the decrease in iron supply becomes a bottleneck for hemoglobin synthesis and eventually results in anemia”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Interpretationnone given§ Figure 6When the rate of iron release from macrophages drops, plasma iron concentrations rapidly decrease.
“When the rate of iron release from macrophages drops, plasma iron concentrations rapidly decrease”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ DiscussionThere 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; and suppression of hepcidin production during hypoxia and anemia.
“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”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Figure 6Transgenic overexpression of IL-6 in mice and repeated administration of IL-6 in rats and cancer patients has been reported to cause anemia.
“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”
Quote in the paperSubstantial claim0 of 2 sources checked
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?
Increased concentrations of hepcidin inhibit ferroportin activity.
“increased concentrations of hepcidin then inhibit ferroportin activity”
From Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis (2021) · cites this paper as [52]
The Introduction (page unavailable) says hepcidin inhibits intestinal iron absorption and the release of recycled iron from macrophages. That supports an inhibitory effect on iron movement, but our copy does not identify ferroportin or say that hepcidin inhibits its activity. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIncreased hepcidin leads to depletion of iron in plasma and extracellular fluid (hypoferremia).
“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]
The section “IL-6 increases hepcidin and induces hypoferremia in humans” reports that IL-6 infusion raised urinary hepcidin while serum iron fell by an average of 34%, supporting reduced circulating iron. The paper does not report iron measurements in extracellular fluid beyond serum, so that part of the claim is not established by our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAs a consequence, absorption of iron from the diet is reduced due to hepcidin mediated reduction of ferroportin expression in enterocytes, reducing circulating iron levels, further aggravated by inhibition of iron export from macrophages.
“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
The Introduction says hepcidin inhibits intestinal iron absorption and release of recycled iron from macrophages, and links inflammation to low serum iron. But the paper does not identify reduced ferroportin expression in enterocytes or macrophages as the mechanism; the Discussion says the role of hepcidin in the enterocyte absorption block remains uncertain. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredInfection and inflammation induce hepcidin predominantly through the effects of the cytokine interleukin-6 (IL-6).
“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]
IL-6 is the main cytokine that stimulates hepcidin synthesis during infection and inflammation.
“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]
Proinflammatory cytokines induced by inflammation can stimulate anemia of inflammation by limiting serum iron and increasing cellular iron stores through modulation of iron regulatory proteins including hepcidin, FPN, ferritin, and DMT1.
“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]
Hepcidin is overexpressed in inflammatory disease and is an early inflammatory marker.
“However, hepcidin is overexpressed in inflammatory disease and is an early inflammatory marker [245,341-345].”
During inflammation, IL-6 signals the liver to release hepcidin, which promotes iron accumulation in phagocytic cells by inducing degradation of the iron exporter ferroportin.
“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
The inflammatory increase in hepcidin is mainly caused by increased IL-6, which induces hepcidin gene transcription through the JAK2/STAT3 pathway.
“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]
IL-6 is important in many infection and inflammation models, but in some models other cytokines may partially replace its stimulatory effect on hepcidin.
“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]
IL-6 mediated induction of hepcidin expression through the JAK/STAT3 pathway is a main contributing factor to pathologic iron homeostasis.
“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]
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.
“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]
All animals received a low-iron diet for 5-7 days before and during experiments to bring baseline hepcidin to normal without causing iron deficiency.
“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]
IL6 is a key mediator of inflammation-driven iron handling, as it induces the production of hepcidin, the master regulator of iron homeostasis.
“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].”
Inflammation-driven dysregulation of iron homeostasis is well established.
“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].”
The study of hepcidin regulation in mice housed under standard conditions is confounded by the high iron content of most commercial mouse chow blends.
“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]
Sustained elevation of hepcidin expression results in anemia due to reduced availability of iron for erythropoiesis.
“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 animal models, diverse inflammatory and infectious stimuli robustly induce hepcidin in the liver via the induction of IL-6, resulting in rapid reduction in serum iron levels.
“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 context of inflammation, interleukin-6 and interleukin-22 stimulate hepcidin expression via specific receptors signaling through STAT-3, while alpha-1 antitrypsin may do so via hemojuvelin and matriptase-2.
“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]
Hepcidin is an acute phase protein upregulated by inflammatory cytokines, notably IL-6.
“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]
During neuroinflammation, glial cells are activated, which perturbs iron homoeostasis.
“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]
Serum sTR concentration reflects total erythroid activity and iron status and reflects plasma iron turnover and erythroid transferrin uptake if iron deficiency is not present.
“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]
Serum sTR concentration reflects total erythroid activity in rats and humans and reflects plasma iron turnover and erythroid transferrin uptake very closely if iron deficiency is not present.
“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]
Induction of hepcidin expression in response to inflammation might explain the anemia of chronic disease.
“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 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.
“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.”
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BackgroundHepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
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“Subsequently, microbial molecules, the plant-derived inflammatory agent turpentine, and cytokines were shown to be potent inducers of hepcidin synthesis (162, 165, 168, 186).”
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“Recent preclinical studies suggest that IL-6 stimulates hepatocytes to produce hepcidin, a polypeptide that inhibits intestinal absorption and reticuloendothelial release of iron (124).”
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“As Albumin-Cre/VHLflox/flox mice exhibit hepatic inflammation and steatosis (21) (Figure 2C), we examined levels of the proinflammatory cytokine IL-6, which is known to stimulate hepcidin expression and may contribute to the anemia of chronic inflammation (5).”
BackgroundInterleukin 6: from bench to bedside
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“IL-6 also induces the secretion of hepcidin, an iron regulatory peptide hormone that is produced in the liver and that negatively regulates the absorption of intestinal iron and iron recycling by macrophages”
BackgroundForging a field: the golden age of iron biology.
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A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression
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“Additional factors/ conditions, including IL-6, c/EBP a , iron, hypoxia, and inflammation, also regulate hepcidin expression (Courselaud et al., 2002; Nemeth et al., 2004a).”
BackgroundInfluentialThe Role of Hepcidin in Iron Metabolism
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“When these mice had an additional gene knocked out encoding a component of the HIF transcriptional complex, hepcidin levels were not suppressed any more. Whether HIF directly regulates hepcidin transcription is still unresolved. One study showed that HIF-1 bound to the mouse and human hepcidin promoters, but another s…”
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Self-citationIron Overload in Human Disease
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Self-citationSTAT3 mediates hepatic hepcidin expression and its inflammatory stimulation
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“and is an early inflammatory marker [245, 341-345].”
BackgroundMoretti, D., Goede, J. S., Zeder, C., Jiskra, M., Chatzinakou, V., Tjalsma, H., Melse-Boonstra, A., Brittenham, G., Swinkels, D. W., & Zimmermann, M. B. (2015) · Blood · doi:10.1182/blood-2015-05-642223 · Cited by 547 · see citing works
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Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis
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“Infection and inflammation induce hepcidin, predominantly through the effects of the cytokine interleukin-6 (IL-6) [52], and increased concentrations of hepcidin then inhibit ferroportin activity, leading to depletion of iron in plasma and extracellular fluid (hypoferremia).”
BackgroundSelf-citationIntracellular iron transport and storage: from molecular mechanisms to health implications
Mackenzie, E. L., Iwasaki, K., & Tsuji, Y. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1893 · Cited by 526 · see citing works
“On binding of wild-type hepcidin, Fpn is phosphorylated and subsequently endocytosed, ubiquitinated, and degraded by the 28S proteasome ( right ). served an increase in hepcidin mRNA, and were able to abro-gate the induction of hepcidin mRNA by treatment with anti–IL-6 antibodies.”
InfluentialRegulation of iron transport and the role of transferrin
Gkouvatsos, K., Papanikolaou, G., & Pantopoulos, K. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.10.013 · Cited by 518 · see citing works
“levels increase in response to iron [158] or inflammation [159], the latter considered as a mechanism of innate immunity to deprive iron from rapidly growing invading pathogens.”
BackgroundTranscriptional regulation by Ferric Uptake Regulator (Fur) in pathogenic bacteria
Troxell, B., & Hassan, H. M. (2013) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2013.00059 · Cited by 500 · see citing works
Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS
Kemna, E., Pickkers, P., Nemeth, E., van der Hoeven, H., & Swinkels, D. (2005) · Blood · doi:10.1182/blood-2005-03-1159 · Cited by 498 · see citing works
Self-citationBekri, S., Gual, P., Anty, R., Luciani, N., Dahman, M., Ramesh, B., Iannelli, A., Staccini–Myx, A., Casanova, D., Ben Amor, I., et al. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.07.007 · Cited by 496 · see citing works
Iron Homeostasis and the Inflammatory Response
Wessling-Resnick, M. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104804 · Cited by 480 · see citing works
“Hepcidin was initially identified as liverderived antimicrobial peptide or LEAP (69, 109, 116) and immediately uncovered as a major product released in response to inflammatory cytokines, in particular interleukin-6 (IL-6) (32, 96, 98, 101).”
BackgroundInfluentialSuppression of hepcidin during anemia requires erythropoietic activity
Pak, M., Lopez, M. A., Gabayan, V., Ganz, T., & Rivera, S. (2006) · Blood · doi:10.1182/blood-2006-06-028787 · Cited by 472 · see citing works
Self-citationViral infection and iron metabolism
Drakesmith, H., & Prentice, A. (2008) · Nature Reviews Microbiology · doi:10.1038/nrmicro1930 · Cited by 469 · see citing works
“Hepcidin is also an acute-phase protein , and is synthesized in inflammatory conditions through interleukin-6- and Toll-like-receptor-4-dependent pathway”
BackgroundHepcidin and disorders of iron metabolism
Ganz, T., & Nemeth, E. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-050109-142444 · Cited by 466 · see citing works
Self-citationRegulation of iron acquisition and storage: consequences for iron-linked disorders
De Domenico, I., McVey Ward, D., & Kaplan, J. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2295 · Cited by 464 · see citing works
Hepcidin and Iron in Health and Disease
Nemeth, E., & Ganz, T. (2023) · Annual Review of Medicine · doi:10.1146/annurev-med-043021-032816 · Cited by 457 · see citing works
Self-citationModulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance
Babitt, J. L., Huang, F. W., Xia, Y. Y., Sidis, Y., Andrews, N. C., & Lin, H. Y.-F. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31342 · Cited by 454 · see citing works
A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors
Kaur, S., Bansal, Y., Kumar, R., & Bansal, G. (2020) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2020.115327 · Cited by 454 · see citing works
Regulation of the Iron Homeostatic Hormone Hepcidin
Sangkhae, V., & Nemeth, E. (2017) · Advances in Nutrition · doi:10.3945/an.116.013961 · Cited by 446 · see citing works
Self-citationHepcidin in iron overload disorders
Papanikolaou, G., Tzilianos, M., Christakis, J. I., Bogdanos, D., Tsimirika, K., MacFarlane, J., Goldberg, Y. P., Sakellaropoulos, N., Ganz, T., & Nemeth, E. (2005) · Blood · doi:10.1182/blood-2004-12-4844 · Cited by 445 · see citing works
Self-citationKautz, L., Meynard, D., Monnier, A., Darnaud, V., Bouvet, R., Wang, R.-H., Deng, C., Vaulont, S., Mosser, J., Coppin, H., et al. (2008) · Blood · doi:10.1182/blood-2008-03-143354 · Cited by 437 · see citing works
Benedetti, F. D., & Ravelli, A. (2000) · BioDrugs · doi:10.2165/00063030-200014020-00003 · Cited by 430 · see citing works
Physical activity and modulation of systemic low-level inflammation
Bruunsgaard, H. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0505247 · Cited by 429 · see citing works
“Studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 induces the iron regulatory peptide hormone hepcidin during inflammation, and the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation [224].”
BackgroundBachman, E., Travison, T. G., Basaria, S., Davda, M. N., Guo, W., Li, M., Connor Westfall, J., Bae, H., Gordeuk, V., & Bhasin, S. (2014) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glt154 · Cited by 426 · see citing works
A Functional Genomic Screen Identifies Cellular Cofactors of Hepatitis C Virus Replication
Tai, A. W., Benita, Y., Peng, L. F., Kim, S.-S., Sakamoto, N., Xavier, R. J., & Chung, R. T. (2009) · Cell Host & Microbe · doi:10.1016/j.chom.2009.02.001 · Cited by 423 · see citing works
“Moreover, the potent upregulation of hepcidin transcription by IL-6 potentially creates a positive feedback loop between chronic inflammation and HCV replication.”
BackgroundHepcidin in the diagnosis of iron disorders
Girelli, D., Nemeth, E., & Swinkels, D. W. (2016) · Blood · doi:10.1182/blood-2015-12-639112 · Cited by 417 · see citing works
“For example, hepcidin production increases substantially within a few hours after iron administration or inflammatory stimulation.(15,28,29,33,34) Because many of the conditions listed in Figure 1 are common, several stimulimay be present simultaneously, with hepcidin output depending on the relative strength of each.”
BackgroundSelf-citationDetection, evaluation, and management of iron-restricted erythropoiesis
Goodnough, L. T., Nemeth, E., & Ganz, T. (2010) · Blood · doi:10.1182/blood-2010-05-286260 · Cited by 410 · see citing works
Self-citationIron homeostasis during pregnancy
Fisher, A. L., & Nemeth, E. (2017) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.117.155812 · Cited by 409 · see citing works
Self-citationInterleukin (IL-6) ImmunotherapyPreprint
Tanaka, T., Narazaki, M., & Kishimoto, T. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028456 · Cited by 407 · see citing works
“Moreover, IL-6-induced hepcidin production blocks the action of iron transporter ferroportin 1 on gut and thus reduces serum iron levels (Nemeth et al. 2004), resulting in hypoferremia and anemia associated with chronic inflammation.”
BackgroundKoskenkorva-Frank, T. S., Weiss, G., Koppenol, W. H., & Burckhardt, S. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.09.001 · Cited by 406 · see citing works
Kremer, J. M., Blanco, R., Brzosko, M., Burgos‐Vargas, R., Halland, A.-M., Vernon, E., Ambs, P., & Fleischmann, R. (2010) · Arthritis & Rheumatism · doi:10.1002/art.30158 · Cited by 405 · see citing works
Nemeth, E., & Ganz, T. (2014) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2014.04.005 · Cited by 401 · see citing works
“The production of hepcidin by hepatocytes is in turn regulated by plasma and hepatic iron concentrations and inflammatory cytokines, chiefly IL-6.”
Self-citationThe struggle for iron - a metal at the host-pathogen interface: Iron at the host-pathogen interface
Nairz, M., Schroll, A., Sonnweber, T., & Weiss, G. (2010) · Cellular Microbiology · doi:10.1111/j.1462-5822.2010.01529.x · Cited by 398 · see citing works
“Binding of hepcidin leads to Fpn1 internalization and proteasomal degradation, thus blocking cellular iron egress (Nemeth et al., 2004b).”
BackgroundHepcidin is decreased in TFR2 hemochromatosis
Nemeth, E., Roetto, A., Garozzo, G., Ganz, T., & Camaschella, C. (2004) · Blood · doi:10.1182/blood-2004-08-3042 · Cited by 396 · see citing works
Self-citationLiver macrophages in health and disease
Guilliams, M., & Scott, C. L. (2022) · Immunity · doi:10.1016/j.immuni.2022.08.002 · Cited by 395 · see citing works
Hepcidin—a regulator of intestinal iron absorption and iron recycling by macrophages
GANZ, T. (2005) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2004.08.020 · Cited by 393 · see citing works
Self-citationTLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens
Peyssonnaux, C., Zinkernagel, A. S., Datta, V., Lauth, X., Johnson, R. S., & Nizet, V. (2006) · Blood · doi:10.1182/blood-2005-06-2259 · Cited by 379 · see citing works
Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease
Podkowińska, A., & Formanowicz, D. (2020) · Antioxidants · doi:10.3390/antiox9080752 · Cited by 378 · see citing works
“Proinflammatory cytokines, especially IL-6, via the signal transducer and activator of the transcription 3 (STAT-3) signaling pathway, are an additional factor stimulating expression of the hepcidin gene [262,263].”
BackgroundRelation Between Red Cell Distribution Width and Clinical Outcomes After Acute Myocardial Infarction
Dabbah, S., Hammerman, H., Markiewicz, W., & Aronson, D. (2009) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2009.09.027 · Cited by 377 · see citing works
Lactoferrin: a natural Glycoprotein involved in iron and inflammatory homeostasis
Rosa, L., Cutone, A., Lepanto, M., Paesano, R., & Valenti, P. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18091985 · Cited by 376 · see citing works
Interleukin-6 as a key player in systemic inflammation and joint destruction
Fonseca, J. E., Santos, M. J., Canhão, H. M., & Choy, E. (2009) · Autoimmunity Reviews · doi:10.1016/j.autrev.2009.01.012 · Cited by 374 · see citing works
Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload
Niederkofler, V. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25683 · Cited by 368 · see citing works
“Injection of LPS, a bacterial endotoxin and potent activator of inflammatory response, induces hepcidin in mice (8), an effect believed to be dependent on cytokine production (4, 5).”
BackgroundLiver iron concentrations and urinary hepcidin in -thalassemia
Origa, R., Galanello, R., Ganz, T., Giagu, N., Maccioni, L., Faa, G., & Nemeth, E. (2007) · Haematologica · doi:10.3324/haematol.10842 · Cited by 365 · see citing works
Self-citationIron Sequestration and Anemia of Inflammation
Ganz, T., & Nemeth, E. (2009) · Seminars in Hematology · doi:10.1053/j.seminhematol.2009.06.001 · Cited by 361 · see citing works
Self-citationLiver iron sensing and body iron homeostasis
Wang, C.-Y., & Babitt, J. L. (2019) · Blood · doi:10.1182/blood-2018-06-815894 · Cited by 360 · see citing works
Iron in infection and immunity
Nairz, M., & Weiss, G. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100864 · Cited by 359 · see citing works
The role of Interleukin 6 in the pathophysiology of rheumatoid arthritis
Srirangan, S., & Choy, E. (2010) · Therapeutic Advances in Musculoskeletal Disease · doi:10.1177/1759720x10378372 · Cited by 357 · see citing works
“IL-6 stimulation induced hepcidin expression has been noted in in vitro studies of human hepatoma cells [Nemeth et al. 2004].”
BackgroundInfluentialNelson, J. E., Wilson, L., Brunt, E. M., Yeh, M. M., Kleiner, D. E., Ünalp–Arida, A., & Kowdley, K. V. (2010) · Hepatology · doi:10.1002/hep.24038 · Cited by 354 · see citing works
“2-4 (20 ) 213 (38) 22 (35) 44 (48) 53 (38)”
InfluentialMolecular control of iron transport
Ganz, T. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006070802 · Cited by 353 · see citing works
“Although the acute hypoferremic response and hepcidin induction both are impaired in IL-6–deficient mice (21), chronic inflammatory stimulation elicits hepcidin even in IL-6–deficient mice (31).”
BackgroundInfluentialSelf-citationTargeting iron metabolism in drug discovery and delivery
Crielaard, B. J., Lammers, T., & Rivella, S. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.248 · Cited by 352 · see citing works
Anemia of inflammation: the cytokine-hepcidin link
Andrews, N. C. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21441 · Cited by 350 · see citing works
“neutralizing antibody against IL-6 blocked hepcidin induction (10).”
InfluentialHepcidin—A Potential Novel Biomarker for Iron Status in Chronic Kidney Disease
Zaritsky, J. J., Young, B. Y., Wang, H.-J., Westerman, M. E., Olbina, G., Nemeth, E., Ganz, T., Rivera, S., Nissenson, A. R., & Salusky, I. B. (2009) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.05931108 · Cited by 349 · see citing works
“Previous studies in populations with normal renal function have shown that oral or parenteral iron loading induces hepcidin production (8,21,29).”
BackgroundSelf-citationMolecular Signatures of Obstructive Sleep Apnea in Adults: A Review and Perspective
Arnardóttir, E. S., Mackiewicz, M., Gíslason, Þ., Teff, K. L., & Pack, A. I. (2009) · SLEEP · doi:10.1093/sleep/32.4.447 · Cited by 347 · see citing works
The Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression
Schmidt, P. J., Toran, P. T., Giannetti, A. M., Bjorkman, P. J., & Andrews, N. C. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.11.016 · Cited by 345 · see citing works
Inflammation and iron deficiency in the hypoferremia of obesity
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Nishimoto, N., Miyasaka, N., Yamamoto, K., Kawai, S., Takeuchi, T., & Azuma, J. (2008) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.092866 · Cited by 333 · see citing works
“Tocilizumab monotherapy markedly improved inflammation markers such as CRP and ESR and improvements were sustained throughout the study. Haemoglobin levels were also improved. It is well documented that hepcidin plays a key role in anaemia of chronic inflammatory diseases. IL-6 induces the secretion of hepcidin, an ir…”
Background
- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- interleukin-6, hepcidin, iron regulation, inflammation, cytokine signaling, liver, iron regulatory hormone
- MeSH terms
- Anemia, Animals, Cell Line, Cells, Cultured, Gene Expression Regulation, Humans, Inflammation, Iron, Kupffer Cells, Mice, Inbred C57BL, Monocytes, RNA, Messenger, Interleukin-6, Mice, Knockout, Iron Metabolism Disorders, Reverse Transcriptase Polymerase Chain Reaction, Hepatocytes, Antimicrobial Cationic Peptides, Mice, Hepcidins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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