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A GATA‐specific inhibitor (K‐7174) rescues anemia induced by IL‐1β, TNF‐α, or l ‐NMMA
Author(s) -
Imagawa Shigehiko,
Nakano Yoko,
Obara Naoshi,
Suzuki Norio,
Doi Takeshi,
Kodama Tatsuhiko,
Nagasawa Toshiro,
Yamamoto Masayuki
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-1134fje
Subject(s) - tumor necrosis factor alpha , erythropoietin , microbiology and biotechnology , reticulocyte , anemia , chemistry , endocrinology , medicine , messenger rna , biology , biochemistry , gene
Interleukin‐1β (IL‐1β), tumor necrosis factor‐α (TNF‐α), 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‐1β, TNF‐α, or l ‐NMMA. Epo protein production and promoter activity were induced in Hep3B cells with 1% O 2 . However, 15 U/ml IL‐1β, 220 U/ml TNF‐α, or 10 −3 M l ‐NMMA inhibited Epo protein production and promoter activity, respectively. Addition of 10 µM K‐7174 rescued these inhibitions of Epo protein production and promoter activity induced by IL‐1β, TNF‐α, 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‐1β, TNF‐α, or l ‐NMMA. Furthermore, intraperitoneal injection of mice with IL‐1β or TNF‐α 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.