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Blood, 1 January 2005, Vol. 105, No. 1, pp. 376-381.
Prepublished online as a Blood First Edition Paper on September 2, 2004; DOI 10.1182/blood-2004-04-1416.
 Previous Article | Next Article 
Submitted April 15, 2004
Accepted August 18, 2004
Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis
Hiroshi Kawabata*, Robert E Fleming, Dorina Gui, Seo Y Moon, Takayuki Saitoh, James O'Kelly, Yutaka Umehara, Yuji Wano, Jonathan W Said, and H. Phillip Koeffler
Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Hematology/Immunology, Kanazawa Medical University, Uchinada, Ishikawa-ken, Japan
Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO, USA
Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, CA, USA
Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Division of Hematology/Immunology, Kanazawa Medical University, Uchinada, Ishikawa-ken, Japan
* Corresponding author; email: hkawabat{at}hotmail.com.
Transferrin receptor 2 (TfR2) is a membrane glycoprotein that can mediate cellular iron uptake from holotransferrin. Homozygous mutations of this gene cause one form of hereditary hemochromatosis in humans. We recently reported that homozygous TfR2(Y245X) mutant mice, which correspond to the TfR2(Y250X) mutation in humans, showed a similar phenotype as hereditary hemochromatosis. In this study, we further analyzed the phenotype as well as iron-related gene expression in these mice by comparing the TfR2-mutant and wild-type siblings. Northern blot analyses showed that the levels of expression of hepcidin mRNA in the liver were generally lower, whereas those of duodenal DMT1, the main transporter for uptake of dietary iron, were higher in the TfR2-mutant mice as compared to the wild-type siblings. Expression of hepcidin mRNA in the TfR2 mutant mice stayed low even after intraperitoneal iron-loading. In isolated hepatocytes from both wild-type and TfR2 mutant mice, interleukin-6 and lipopolysaccharide each induced expression of hepcidin mRNA. These results suggest that up-regulation of hepcidin expression by inflammatory stimuli is independent of TfR2, and that TfR2 is upstream of hepcidin in the regulatory pathway of body iron homeostasis.
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