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

Shigehiko Imagawa, Yoko Nakano, Naoshi Obara, Norio Suzuki, Takeshi Doi, Tatsuhiko Kodama, Toshiro Nagasawa, Masayuki Yamamoto

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1742-1744
Number of pages3
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume17
Issue number12
DOIs
Publication statusPublished - 2003 Sep
Externally publishedYes

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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