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.
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Authors | Shigehiko Imagawa, Yoko Nakano, Naoshi Obara, Norio Suzuki, Takeshi Doi, Tatsuhiko Kodama, Toshiro Nagasawa, Masayuki Yamamoto |
Journal | FASEB 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 |
PMID | 12958195
(Publication Type: Journal Article)
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Chemical References |
- Anisoles
- Azepines
- DNA-Binding Proteins
- Hemoglobins
- Interleukin-1
- Transcription Factors
- Tumor Necrosis Factor-alpha
- Erythropoietin
- omega-N-Methylarginine
- K 7174
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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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