Interleukin-1β inhibits the hypoxic inducibility of the erythropoietin enhancer by suppressing hepatocyte nuclear factor-4α

The suppression of hypoxia-induced erythropoietin (EPO) expression by inflammatory cytokines like interleukin-1 (IL-1) contributes to the development of the anemia of chronic disease (ACD). However, the precise mechanism of this suppression is unclear. The 3'-EPO enhancer mediates the transcriptional response to hypoxia by binding several transcription factors, including hypoxia-inducible factor, hepatocyte nuclear factor-4α (HNF-4α) and chicken ovalbumin upstream promoter transcription factor. We investigated whether IL-1β inhibits the activity of the 3'-EPO enhancer via HNF-4α. IL-1β inhibited HNF-4α mRNA expression and caused proteasome-dependent degradation of HNF-4α protein, which resulted in a strongly reduced DNA-binding activity of HNF-4α. Reporter gene assays revealed that IL-1β caused a complete suppression of the hypoxic inducibility of the 3′ enhancer via inhibition of HNF-4α. We conclude that IL-1β, at least partially, reduces hypoxia-induced EPO expression by down-regulation of HNF-4α.