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Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidin-mediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-a transcript and secreted protein. Hepci-din-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses., Introduction Hepcidin is a peptide hormone secreted by a wide variety of cells, most predominantly by hepatocytes. Hepcidin has two functions. First, iron homeostasis in vertebrates is regulated by the [...]

Mutations that have recently increased in frequency by positive natural selection are an important component of naturally occurring variation that affects fitness. To identify such variants, we developed a method to test for recent selection by estimating the age of an allele from the extent of haplotype sharing at linked sites. Neutral coalescent simulations are then used to determine the likelihood of this age given the allele's observed frequency. We applied this method to a common disease allele, the hemochromatosis-associated HFE C282Y mutation. Our results allow us to reject neutral models incorporating plausible human demographic histories for HFE C282Y and one other young but common allele, indicating positive selection at HFE or a linked locus. This method will be useful for scanning the human genome for alleles under selection using the haplotype map now being constructed.

Many relatives of patients with hemochromatosis have a condition related to hemochromatosis, including liver cirrhosis, liver fibrosis, and joint disease. Hemochromatosis is a genetic disorder that causes excessive iron deposits in various organs.

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People who are heterozygous for hemochromatosis, an excess of iron deposits in the body, have distinct clinical and biochemical abnormalities. The genetic mutation is found on chromosome 6. Iron in the blood and transferritin-saturation values were higher in 1,058 heterozygotes than in 321 normal people, especially among men. Clinical and biochemical abnormalities were more distinct in people who had inherited the disease from their father's side. Liver damage was minimal in this group, unless caused by alcohol or other pathological conditions.

Widespread screening for hereditary hemochromatosis could lead to fewer complications and deaths among patients with this disease. Hereditary hemochromatosis is a fairly common genetic disorder that is characterized by increased absorption of iron by the intestines. It can cause complications such as abnormalities in skin pigmentation, cirrhosis of the liver, diabetes, endocrine gland failure, heart failure and joint disease. Hemochromatosis is caused by a mutation in a gene located on chromosome six. Hemochromatosis patients have higher transferrin saturation and blood levels of ferritin; these levels can be tested. Measurement of transferrin saturation is the most sensitive test. Identification of asymptomatic individuals with hereditary hemochromatosis would aid early treatment for the disease. Patients with accumulation of iron in the liver should be treated with whole-blood phlebotomy (removal of blood).

Author(s): John D Phillips [1]; James P Kushner [1] Hemoglobin and other hemoproteins mediate functions as diverse as transcription, respiration, and drug and hormone metabolism. A key component of such [...]