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A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1beta, TNF-alpha, or L-NMMA.

Abstract
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.
AuthorsShigehiko Imagawa, Yoko Nakano, Naoshi Obara, Norio Suzuki, Takeshi Doi, Tatsuhiko Kodama, Toshiro Nagasawa, Masayuki Yamamoto
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 17 Issue 12 Pg. 1742-4 (Sep 2003) ISSN: 1530-6860 [Electronic] United States
PMID12958195 (Publication Type: Journal Article)
Chemical References
  • Anisoles
  • Azepines
  • DNA-Binding Proteins
  • Hemoglobins
  • Interleukin-1
  • K 7174
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Erythropoietin
  • omega-N-Methylarginine
Topics
  • Anemia (chemically induced, drug therapy, metabolism)
  • Animals
  • Anisoles (pharmacology, therapeutic use)
  • Azepines (pharmacology, therapeutic use)
  • Binding Sites
  • Cell Count
  • Cell Hypoxia
  • Cell Line
  • DNA-Binding Proteins (antagonists & inhibitors, metabolism)
  • Erythropoietin (biosynthesis, genetics)
  • Hemoglobins (analysis)
  • Interleukin-1 (antagonists & inhibitors)
  • Mice
  • Models, Genetic
  • Promoter Regions, Genetic
  • Reticulocytes (cytology)
  • Transcription Factors (antagonists & inhibitors, metabolism)
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors)
  • omega-N-Methylarginine (antagonists & inhibitors)

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