Kawabata Hiroshi, Fleming Robert E, Gui Dorina, Moon Seo Y, Saitoh Takayuki, O'Kelly James, Umehara Yutaka, Wano Yuji, Said Jonathan W, Koeffler H Phillip
Division of Hematology/Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Blood. 2005 Jan 1;105(1):376-81. doi: 10.1182/blood-2004-04-1416. Epub 2004 Sep 2.
Transferrin receptor 2 (TfR2) is a membrane glycoprotein that mediates 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 phenotype similar to 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 remained 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.
转铁蛋白受体2（TfR2）是一种膜糖蛋白，介导细胞从全转铁蛋白摄取铁。该基因的纯合突变会导致人类一种遗传性血色素沉着症。我们最近报道，与人类TfR2（Y250X）突变相对应的纯合TfR2（Y245X）突变小鼠表现出与遗传性血色素沉着症相似的表型。在本研究中，我们通过比较TfR2突变体和野生型同窝小鼠，进一步分析了这些小鼠的表型以及铁相关基因的表达。Northern印迹分析表明，与野生型同窝小鼠相比，TfR2突变小鼠肝脏中铁调素mRNA的表达水平普遍较低，而十二指肠中主要负责摄取膳食铁的转运体DMT1的表达水平较高。即使在腹腔注射铁后，TfR2突变小鼠中铁调素mRNA的表达仍保持较低水平。在野生型和TfR2突变小鼠的分离肝细胞中，白细胞介素-6和脂多糖均可诱导铁调素mRNA的表达。这些结果表明，炎症刺激对铁调素表达的上调与TfR2无关，并且在机体铁稳态的调节途径中，TfR2位于铁调素的上游。
