Significance of the mechanisms of iron homeostasis in malignancies and inflammatory diseases.

本研究的目的是阐明铁调节分子（如HFE、TfR 2和hepcidin）调节机体铁稳态的机制，并阐明该机制在恶性肿瘤和炎症性疾病中的临床意义。铁调素是一种调节机体铁稳态的肽类激素，其在肝脏中的表达可被炎性细胞因子白细胞介素-6（IL-6）诱导。与Tomosugi博士（金泽医科大学）合作，我们开发了一种使用SELDI-TOF质谱法的血清铁调素半定量测定系统（Blood，2006）。使用该系统，我们分析了Castleman病（一种伴有严重贫血的慢性炎症性疾病）患者在用抗IL-6受体抗体治疗前后的血清和尿铁调素水平（在福冈2006年68^<th>JSH和48^<th>JSCH上的口头报告，在京都BioIron 2007上的口头报告，Haematologica，出版中）。我们证明，施用抗IL-6受体抗体迅速下调血清和尿铁调素的水平，随后显著改善炎症症状以及小细胞性贫血。我们现在正在用这种方法分析各种炎症和造血系统疾病的血清和尿铁调素水平。TfR 2是我们最初克隆的一种分子，已知该基因的突变会导致遗传性血色素瘤病。我们假设TfR 2是铁转铁蛋白的传感器，可以诱导铁调素的表达。利用四环素诱导的TfR 2表达系统，我们现在正试图阐明从铁感应到铁调素分泌的途径。

The purpose of this study was to clarify the mechanism how iron regulatory molecules (such as HFE, TfR2 and hepcidin) regulate body iron homeostasis and to clarify the clinical significance of this mechanism in malignancies and inflammatory diseases. Hepcidin is a peptide hormone regulating body iron homeostasis and its expression in the liver can be induced by inflammatory cytokine interleukin-6 (IL-6). In collaboration with Dr. Tomosugi (Kanazawa Medical University), we developed a semi-quantitative assay system for serum hepcidin using SELDI-TOF mass-spectrometry (Blood, 2006). Employing this system, we analyzed the level of serum and urine hepcidin in patients with Castleman's disease, a chronic inflammatory disorder with severe anemia, before and after treatment with an anti-IL-6 receptor antibody (Oral presentation at 68^<th> JSH and 48^<th> JSCH at Fukuoka 2006, Oral presentation at BioIron 2007 at Kyoto, Haematologica, in press). We demonstrated that administration of the anti-IL-6 receptor antibody quickly downregulated the levels of serum and urine hepcidin followed by dramatic improvement of inflammatory symptoms as well as microcytic anemia. We are now analyzing the levels of serum and urine hepcidin with this method in a variety of inflammatory and hematopoietic diseases. TfR2 is a molecule that we originally cloned and mutation of this gene has been known to cause hereditary hemochomatosis. We have hypothesized that TfR2 is a sensor of ferric transferrin and can induce expression of hepcidin. Using tetracycline inducible TfR2 expressing systems, we are now trying to clarify the pathway from iron sensing to hepcidin secretion in the liver.