SIGNALING PATHWAYS MEDIATED BY THE TNF-RECEPTOR AND CYTOKINE-RECEPTORFAMILIES TARGET A COMMON CIS-ELEMENT OF THE IFN REGULATORY-FACTOR-1 PROMOTER

CD40 activation of B cells is strongly influenced by the presence of c ytokines. However, the molecular basis for the interplay between these distinct stimuli is not clearly delineated, IFN regulatory factor 1 ( IRF-1) is a transcription factor activated by either CD40 or cytokines , We have found that these different sets of signals target a common c is-acting element in the promoter of this gene, the IRF-1 gamma-activa ted site (GAS), Targeting of the IRF-1 GAS is not confined to activati on via CD40 but extends to other stimuli that mimic the CD40 signaling cascade, like TNF-alpha and EBV, In contrast to induction of STATs by cytokines, the IRF-1 GAS-binding complex activated by CD40, TNF-cu, o r EBV contains Rer proteins, specifically p50 and p65, In this system, simultaneous exposure to CD40L together with either IL-4 or IFN-gamma does not lead to the activation of novel Rel/STAT complexes. Given th e importance of IRF-1 in a variety of biologic functions from prolifer ation to apoptosis, our findings support the notion that modulation of IRF-1 levels may be a critical control point in B cell activation.