ACTIVATION OF CAAT ENHANCER-BINDING PROTEIN-DELTA (C EBP-DELTA) BY INTERLEUKIN-1 NEGATIVELY INFLUENCES APOLIPOPROTEIN C-III EXPRESSION/

Tissue specific transcription of the apolipoprotein C-III (apoC-III) g ene is mainly regulated by synergistic interactions between the liver- enriched transcription factor HNF-4, which binds to the proximal promo ter, and ubiquitous factors, which bind to the upstream enhancer regio n, Here we show that apoC-III expression in HepG2 cells is negatively regulated in response to interleukin-1 (IL-1), and this inhibition is mainly due to transcriptional repression, CAAT enhancer-binding protei n delta (C/EBP delta) was found to be the main mediator of IL-1-induce d suppression. Analysis of the apoC-III promoter revealed two IL-1 res ponse elements, The first is located in the proximal promoter region D and the second in the distal enhancer region I, Proximal element D is a high affinity binding site for C/EBP delta, while the enhancer elem ent I is not directly recognized by this transcription factor, Functio nal analysis of different combinations of homologous and heterologous promoter constructs revealed that indirect interaction of C/EBP delta with site I, in the context of the full promoter, leads to repression. C/EBP delta is activated by phosphorylation during IL-1-induced signa l transduction pathway, This modification is important for bath DNA bi nding activity and indirect transrepression of the apoC-III promoter.