A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1beta, TNF-alpha, or L-NMMA.
Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), or N(G)-monomethyl-L-arginine (L-NMMA) are increased in patients with chronic disease-related anemia. They increase the binding activity of GATA and inhibit erythropoietin (Epo) promoter activity. In this study, we examined the ability of K-7174 (a GATA-specific inhibitor) to improve Epo production when inhibited by treatment with IL-1beta, TNF-alpha, or L-NMMA. Epo protein production and promoter activity were induced in Hep3B cells with 1% O2. However, 15 U/ml IL-1beta, 220 U/ml TNF-alpha, or 10(-3) M L-NMMA inhibited Epo protein production and promoter activity, respectively. Addition of 10 microM K-7174 rescued these inhibitions of Epo protein production and promoter activity induced by IL-1beta, TNF-alpha, or L-NMMA, respectively. Electrophoretic mobility shift assays revealed that addition of K-7174 decreased GATA binding activity, which was increased with the addition of IL-1beta, TNF-alpha, or L-NMMA. Furthermore, intraperitoneal injection of mice with IL-1beta or TNF-alpha decreased the hemoglobin concentrations and reticulocyte counts. However, the addition of K-7174 reversed these effects. These results raise the possibility of using K-7174 as therapy to treat anemia.
Imagawa
Shigehiko
S
Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. simigawa@md.tsukuba.ac.jp
Nakano
Yoko
Y
Obara
Naoshi
N
Suzuki
Norio
N
Doi
Takeshi
T
Kodama
Tatsuhiko
T
Nagasawa
Toshiro
T
Yamamoto
Masayuki
M
D000740:Anemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000840:Anisoles / Q000494:pharmacology / Q000627:therapeutic use*; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use*; D001665:Binding Sites; D002452:Cell Count; D015687:Cell Hypoxia; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics; D006454:Hemoglobins / Q000032:analysis; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D051379:Mice; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D012156:Reticulocytes / Q000166:cytology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D019323:omega-N-Methylarginine / Q000037:antagonists & inhibitors
D000840:Anisoles; D001381:Azepines; D004268:DNA-Binding Proteins; D006454:Hemoglobins; D007375:Interleukin-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D019323:omega-N-Methylarginine; C410337:K 7174