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.
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
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: