Abstract.
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.
Keywords. Erythropoietin, anemia of chronic disease, interleukin-1, hepatocyte nuclear factor-4, hypoxia inducible factor-1, chicken ovalbumin upstream promoter transcription factor
Footnotes
Received 22 December 2006; received after revision 22 February 2007; accepted 1 March 2007