Nakano Yoko, Imagawa Shigehiko, Matsumoto Ken, Stockmann Christian, Obara Naoshi, Suzuki Norio, Doi Takeshi, Kodama Tatsuhiko, Takahashi Satoru, Nagasawa Toshiro, Yamamoto Masayuki
Division of Hematology, Institute of Clinical Medicine, Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Blood. 2004 Dec 15;104(13):4300-7. doi: 10.1182/blood-2004-04-1631. Epub 2004 Aug 24.
Erythropoietin (Epo) gene expression is under the control of hypoxia-inducible factor 1 (HIF-1), and is negatively regulated by GATA. Interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha), which increase the binding activity of GATA and inhibit Epo promoter activity, are increased in patients with anemia of chronic disease (ACD). We previously demonstrated the ability of K-7174 (a GATA-specific inhibitor), when injected intraperitoneally, to improve Epo production that had been inhibited by IL-1beta or TNF-alpha treatment. In the present study, we examined the ability of both K-11706, which inhibits GATA and enhances HIF-1 binding activity, and K-13144, which has no effect on GATA or HIF-1 binding activity, to improve Epo production following inhibition by IL-1beta or TNF-alpha in Hep3B cells in vitro and in an in vivo mouse assay. Oral administration of K-11706 reversed the decreases in hemoglobin and serum Epo concentrations, reticulocyte counts, and numbers of erythroid colony-forming units (CFU-Es) induced by IL-1beta or TNF-alpha. These results raise the possibility of using orally administered K-11706 for treating patients with ACD.
促红细胞生成素（Epo）基因表达受缺氧诱导因子1（HIF-1）调控，并受GATA负调控。白细胞介素1β（IL-1β）和肿瘤坏死因子α（TNF-α）可增加GATA的结合活性并抑制Epo启动子活性，在慢性病贫血（ACD）患者中水平升高。我们之前证明，腹腔注射K-7174（一种GATA特异性抑制剂）能够改善因IL-1β或TNF-α处理而受到抑制的Epo生成。在本研究中，我们检测了抑制GATA并增强HIF-1结合活性的K-11706以及对GATA或HIF-1结合活性无影响的K-13144在体外Hep3B细胞和体内小鼠实验中改善IL-1β或TNF-α抑制后的Epo生成的能力。口服K-11706可逆转由IL-1β或TNF-α诱导的血红蛋白和血清Epo浓度降低、网织红细胞计数以及红系集落形成单位（CFU-E）数量减少。这些结果提示口服K-11706治疗ACD患者具有可能性。
