Interferon ␥ (IFN␥)5 regulates a range of cellular activities including anti-viral and anti-microbial immunity, apoptosis, and cell cycle progression through the induction of IFN-stimulated genes (ISGs) (1). Typically, IFN␥ signaling proceeds through the ligation of surface receptors, sequential phosphorylation of JAKs and STAT1 on tyrosine 701 (Tyr-701), and translocation of STAT1 homodimers to the nucleus to bind IFN␥-activated sequences (GASs) found in the promoter regions of many ISGs (1, 2). However, other signaling pathways are important for IFN␥ signaling. For example STAT1 requires phosphorylation on Ser-727 to achieve full transcriptional activity (3, 4). Additionally, microarray analysis revealed that approximately one-third of ISGs were still regulated by IFN␥ in the absence of functional STAT1 (5-7), and STAT1 Ϫ/Ϫ mice were more resistant to virus infection than mice lacking expression of the IFN␥ and IFN␣/ receptors (5, 8). Thus, IFN␥ can induce expression of ISGs by STAT1-independent mechanisms, and the activity of multiple intracellular pathways acting in parallel play an important role in the biological response to IFN␥.Aside from the JAKs, other kinases are activated in response to IFN␥, including MAP kinases (9 -11), phosphatidylinositol 3-kinase and AKT (12), Pyk2 (11), calcium/calmodulindependent protein kinase II (13), and protein kinase C isoforms (14, 15). However, these enzymes have predominantly been assessed for their ability to trigger phosphorylation of STAT1 on Ser-727, and little is known about their potential impact upon STAT-independent gene transcription. IFN␥ can activate transcription factors other than STAT1, including, class II trans-activator (CIITA) (16 -18), CCAAT enhancer-binding protein (CEBP)- (19 -21), and interferon-responsive factors (IRFs) (22, 23), but the induction of these factors occurs downstream of JAK-STAT1 signaling. There are conflicting reports regarding the involvement of the IKK/IB/NF-B pathway in STAT1-independent IFN␥ signaling (24 -26). Recently, it was shown that activation of IKK␣ and IKK in the absence of NF-B activity was important for the induction of a subset of ISGs following treatment with IFN␥ (26). However the signaling proteins and transcription factors downstream of IKK activation by IFN␥ were not identified, and although STAT1 was phosphorylated on Tyr-701 and Ser-727 in IFN␥-treated IKK␣/