A polymorphism in the promoter of the UDPglucuronosyltransferase 1 (UGT1A1) gene has been shown to cause Gilbert syndrome, a benign form of unconjugated bilirubinemia. Promoters containing seven thymine adenine (ta) repeats have been found to be less active than the wild-type six repeats, and the serum bilirubin levels of persons homozygous or even heterozygous for seven repeats have been found to be higher than those with the wild-type six repeats. We have now examined the genotypes in persons of Asian, African, and Caucasian ancestry. Although within the Caucasian ethnic group there is a strong correlation between promoter repeat number and bilirubin level, between ethnic groups we found that this relationship to be inverse. Among people of African ancestry there are, in addition to those with six and seven repeats, also persons who have five or eight repeats. Using a reporter gene we show that there is an inverse relationship between the number of ta repeats and the activity of the promoter through the range of 5-8 ta repeats. An incidental finding was a polymorphism at nucleotide ؊106, tightly linked to the (ta) 5 haplotype. Serum bilirubin levels are inf luenced by many factors, both genetic and environmental. We suggest that the unstable UGT1A1 polymorphism may serve to ''fine-tune'' the plasma bilirubin level within population groups, maintaining it at a high enough level to provide protection against oxidative damage, but at a level that is sufficiently low to prevent kernicterus in infants.

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Hepcidin, a liver-derived protein that restricts enteric iron absorption, is the key regulator of body iron content. Several proteins induce expression of the hepcidin-encoding gene Hamp in response to infection or high levels of iron. However, mechanism(s) of Hamp suppression during iron depletion are poorly understood. We describe mask: a recessive, chemically induced mutant mouse phenotype, characterized by progressive loss of body (but not facial) hair and microcytic anemia. The mask phenotype results from reduced absorption of dietary iron caused by high levels of hepcidin and is due to a splicing defect in the transmembrane serine protease 6 gene Tmprss6. Overexpression of normal TMPRSS6 protein suppresses activation of the Hamp promoter, and the TMPRSS6 cytoplasmic domain mediates Hamp suppression via proximal promoter element(s). TMPRSS6 is an essential component of a pathway that detects iron deficiency and blocks Hamp transcription, permitting enhanced dietary iron absorption.

Hepcidin is a peptide that regulates iron homeostasis by inhibiting iron absorption by the small intestine and release of iron from macrophages. Its production is stimulated by iron overload and by inflammation. It has been suggested that IL-6 is the only cytokine that stimulates hepcidin transcription. However, mice with targeted disruption of the gene encoding IL-6 (IL-6 ؊/؊ ) respond to endotoxin by increasing the expression of hepcidin transcripts in the liver. We show that incubating murine hepatocytes with IL-6, IL-1␣, and IL-1␤ strongly stimulates hepcidin transcription. IL-10 has little or no stimulatory effect, and IFN-␤ inhibits transcription of hepcidin. All of the hepcidin stimulatory activity of macrophages from IL-6 ؊/؊ mice can be accounted for by IL-1 that they secrete. Hepatocytes from IL-6 ؊/؊ mice, hfe ؊/؊ mice, and mice with a hypomorphic transferrin receptor 2 mutation responded to IL-6 and IL-1 by up-regulating hepcidin transcription. Nitric oxide does not seem to be involved in the stimulation of hepcidin transcription by cytokines: aminoguanidine does not inhibit the stimulation of hepcidin transcription by cytokines. IL-1 may play a significant role in the anemia of inflammation by up-regulating hepcidin.HFE ͉ iron ͉ liver ͉ nitric oxide H epcidin has emerged as a central regulator of iron homeostasis. First described as a 25-amino acid antimicrobial peptide (1, 2), it was subsequently found to be a powerful negative regulator of iron absorption (3, 4). Befitting its role as an antimicrobial peptide, hepcidin is up-regulated in intact animals by the injection of endotoxin or turpentine.Moreover, culture media conditioned by treatment of macrophages with LPS stimulate hepcidin transcription in cultures of primary hepatocytes (5). Because this stimulation was entirely blocked by anti-IL-6 antibody, it was concluded that the stimulation was due to IL-6 and that stimulation did not occur with IL-1 and TNF-␣ (6). Our data suggested, however, that some stimulation of hepcidin production occurred in IL-6 Ϫ/Ϫ mice treated with LPS (7). These data have recently been confirmed by Rivera et al.† Accordingly, there must be substances other than IL-6 that stimulate hepcidin production. We now show that hepatocytes can be stimulated directly to produce hepcidin message by the cytokines IL-6, IL-1␣, and IL-1␤ and that the stimulation of hepcidin production by macrophage-conditioned media can be accounted for entirely by these three cytokines. Materials and MethodsAll cytokines and cytokine-specific antibodies were obtained from R & D Systems. Aminoguanidine hemisulfate was purchased from Calbiochem. IL-6 Ϫ/Ϫ mice were on a background of C57BL͞6J (002650) and were obtained from The Jackson Laboratory. hfe Ϫ/Ϫ mice and transferrin receptor 2 (tfr2) mutant mice were kind gifts from Dr. William Sly (Saint Louis University, St. Louis) and Dr. Robert Fleming (Saint Louis University), respectively. The hfe Ϫ/Ϫ mice had been backcrossed into the 129 strain for 10 generations; the tfr2 mutant mice, transgenic m...

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