The CCAAT/enhancer-binding protein delta (C/EBP delta) transcription factor is known to be rarely expressed but sharply induced at an early stage of the acute phase response. To investigate the regulation mechanisms for this induction, the 5'-flanking region of the rat C/EBP delta gene was isolated. Functional analyses involving transfection and footprinting indicated that the upstream region up to - 175 bp is sufficient for the full basal activity in rat fibroblast 3Y1 cells. At least three cis-elements including a GC box are involved in this activity. When HepG2 cells were treated with interleukin-6 (IL-6), C/EBP delta mRNA was rapidly induced. Transfection and gel shift analyses identified the binding site for the acute phase response factor/signal transducers and activators of transcription (APRF/STAT3). These findings strongly indicate that C/EBP delta gene expression is mediated by APRF/STAT3, which is phosphorylated for the activation through the IL-6 receptor when cells are treated with IL-6, and trans-activates the other acute phase response genes.

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