Interaction of AP-1 with a cluster of NF-kappa B binding elements in the human TNF promoter region.

Transcriptional activation of the human TNF gene involves multiple regulatory elements whose functional properties vary between stimuli and cell types. Here we have used a COS-7 expression system to dissect the transactivating potential of NF-kappa B binding sites in the human TNF promoter region from other regulatory influences. In this model, NF-kappa B acts largely through a dense cluster of three binding sites located 600 nt upstream of the transcription start site. We show that the transcriptional activity of this complex is highly sensitive to the p65:p50 ratio that is expressed. We demonstrate that the AP-1 complex c-Jun/Fra2 is capable of binding to this region and that this inhibits the transactivating effects of NF-kappa B. These results are suggestive of a complex regulatory element that mediates fine control rather than acting as a simple on-off switch for TNF gene expression