IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin

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 supported

  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)

  cites [7] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [8] Nicolas, 2002, J. Clin. Invest. sourceExperimental — accuracy not yet measured

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 supported

  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)

  cites [8] Nicolas, 2002, J. Clin. Invest. sourceExperimental — accuracy not yet measured

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 supported

  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)

  cites [7] sourceExperimental — accuracy not yet measured

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

• Supported

  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)

  cites [8] Nicolas, 2002, J. Clin. Invest. source

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 verify

  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)

  cites [12] sourceExperimental — accuracy not yet measured

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”

In the paper

“serum iron decreased on average 34% and transferrin saturation decreased 33% in comparison to preinfusion values”

In the paper

“TNFα markedly suppressed hepcidin mRNA levels by a mechanism that did not involve IL-6 regulation”

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”

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”

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”

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

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

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

In the paper

“These observations suggest that human hepcidin is the functional equivalent of hepcidin-1 in mice.”

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

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

In the paper

“Hepatic hepcidin mRNA levels in mice were shown to increase in response to increased dietary iron”

What the sources say

• ?Not checked — no full text of the sourcecites [3] source
• ?Not checked — no full text of the sourcecites [26] source

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”

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”

In the paper

“the decrease in iron supply becomes a bottleneck for hemoglobin synthesis and eventually results in anemia”

In the paper

“When the rate of iron release from macrophages drops, plasma iron concentrations rapidly decrease”

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”

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

• ?Not checked — no full text of the sourcecites [36] source
• ?Not checked — no full text of the sourcecites [33] Nieken, 1995, Blood. source