Interleukin-1beta inhibits the hypoxic inducibility of the erythropoietin enhancer by suppressing hepatocyte nuclear factor-4alpha.
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-4alpha (HNF-4alpha) and chicken ovalbumin upstream promoter transcription factor. We investigated whether IL-1beta inhibits the activity of the 3'-EPO enhancer via HNF-4alpha. IL-1beta inhibited HNF-4alpha mRNA expression and caused proteasome-dependent degradation of HNF-4alpha protein, which resulted in a strongly reduced DNA-binding activity of HNF-4alpha. Reporter gene assays revealed that IL-1beta caused a complete suppression of the hypoxic inducibility of the 3' enhancer via inhibition of HNF-4alpha. We conclude that IL-1beta, at least partially, reduces hypoxia-induced EPO expression by down-regulation of HNF-4alpha.
Krajewski
J
J
Institute of Physiology, University of Luebeck, Ratzeburger Allee 160, Luebeck, Germany.
Batmunkh
C
C
Jelkmann
W
W
Hellwig-Bürgel
T
T
D000740:Anemia / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D004921:Erythropoietin / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics
C497442:HIF1A protein, human; D051557:Hepatocyte Nuclear Factor 4; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D007976:Leupeptins; D008164:Luminescent Proteins; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C413663:fluorescent protein 583; D004921:Erythropoietin; D004247:DNA; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde