Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease.
Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease.
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DOI：
10.1182/blood-2004-04-1631
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发表时间：
2004-12
期刊：
影响因子：
20.3
通讯作者：
Y. Nakano;S. Imagawa;Ken Matsumoto;C. Stockmann;N. Obara;N. Suzuki;T. Doi;T. Kodama;Satoru Takahashi;T. Nagasawa;Masayuki Yamamoto
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文献类型：
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作者：
Y. Nakano;S. Imagawa;Ken Matsumoto;C. Stockmann;N. Obara;N. Suzuki;T. Doi;T. Kodama;Satoru Takahashi;T. Nagasawa;Masayuki Yamamoto
促红细胞生成素（Epo）基因的表达受缺氧诱导因子1（HIF-1）的调控，并受加塔（GATA）负调控。白细胞介素1 β（IL-1 β）和肿瘤坏死因子α（TNF-α）可增加加塔的结合活性并抑制Epo启动子活性，在慢性病贫血（ACD）患者中升高。我们先前证明了K-7174（一种GATA特异性抑制剂）在腹腔注射时能够改善IL-1 β或TNF-α治疗抑制的Epo产生。在本研究中，我们在体外和小鼠体内试验中检测了K-11706（抑制加塔并增强HIF-1结合活性）和K-13144（对加塔或HIF-1结合活性无影响）改善Hep 3B细胞中IL-1 β或TNF-α抑制后Epo产生的能力。K-11706经口给药可逆转IL-1 β或TNF-α诱导的血红蛋白和血清Epo浓度、网织红细胞计数和红系集落形成单位（CFU-Es）数量的降低。这些结果提高了口服K-11706治疗ACD患者的可能性。
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.