CD40 Stimulates a Feed-Forward NF-κB-Driven Molecular Pathway That Regulates IFN-β Expression in Carcinoma Cells

INF-beta and the CD401 (CD154) share important roles in the antiviral and antitumor immune responses. In this study, we show that CD40 receptor occupancy results in IFN-beta upregulation through an unconventional feed-forward mechanism, which is orchestrated by canonical NF-kappa B and involves the sequential de novo synthesis of IFN regulatory factor (IRF)1 and Viperin (RSAD2), an IRF1 target. RelA (p65) NF-kappa B, IRF1, and Viperin-dependent IRF7 binding to the IFN-beta promoter largely controls its activity. However, full activation of IFN-beta also requires the parallel engagement of noncanonical NF-kappa B2 signaling leading to p52 recruitment to the IFN-beta promoter. These data define a novel link between CD40 signaling and IFN-beta expression and provide a telling example of how signal propagation can be exploited to ensure efficient regulation of gene expression. The Journal of Immunology, 2012, 188: 5521-5527.