Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA‐2 and NF‐κB

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Abstract
The anemia of chronic inflammatory and malignant diseases is partly due to impaired synthesis of the hormone erythropoietin (Epo). The proinflammatory cytokines interleukin‐1 (IL‐1) and tumor necrosis factor α (TNF‐α) suppress in vitro Epo gene expression and Epo protein secretion. However, the molecular mechanisms of this inhibition are poorly understood. The human Epo promoter and the 5' flanking region contain several recognition sequences for transcription factors acting either positively or negatively. Herein, we investigated the roles of the transcription factors GATA‐2 and NF‐κB in the modulation of Epo gene expression by IL‐1β and TNF‐α in the human hepatoma cell line HepG2. Electrophoretic mobility shift assays revealed increased GATA‐2 and NF‐κB DNA binding in cells treated with IL‐1β or TNF‐α. Reporter gene assays with a sequence from the Epo promoter in front of the firefly luciferase gene showed that the cytokines reduced Epo reporter gene activity. Functional inactivation of GATA‐2 and NF‐κB by oligo‐decoy techniques prevented the inhibition of Epo production by IL‐1β and TNF‐α. In HepG2 cells stably transfected with a dominant‐negative form of IκBα, the activation of NF‐κB was inhibited, while Epo mRNA levels and Epo secretion increased. Thus, both GATA‐2 and NF‐κB seem to be involved in the suppression of Epo gene expression by IL1β and TNF‐α in vitro and may be responsible for impaired Epo synthesis in inflammatory diseases in vivo.
Funding Information
  • Deutsche Forschungsgemeinschaft (SFB 367-C8)

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