Activation of a subset of genes by IFN-γ requires IKKβ but not interferon-dependent activation of NF-κB

Activation of NF-kappa B requires the inhibitor of kappa B (I kappa B) kinase (IKK) complex, which is made up of two functional kinases, IKK alpha and IKK beta, and the scaffolding protein IKK gamma. We recently identified several interferon-gamma (IFN-gamma)-stimulated genes (ISGs) that are not induced in mouse embryonic fibroblast cells (MEFs) doubly null for the expression of IKK alpha and IKK beta. We show here that the IFN-gamma-induced transcription of IKK-dependent ISGs requires IKK beta but not IKK alpha. We also identify several additional IKK beta-dependent ISGs that are induced by IFN-gamma both in MEFs and in RAW 264.7 macrophages. Many have a combination of kappa B and IFN-stimulated response elements (ISRE) in their promoters. Although the IFN-gamma-induced expression of the IKK beta-dependent gene ip-10 is sensitive to the superrepressor (SR) of I kappa B alpha and requires the p65 subunit of NF-kappa B, IFN-gamma does not activate NF-kappa B. In summary, a distinct subset of IFN-gamma-dependent genes requires some components of the normal pathway of NF-kappa B activation without activation of NF-kappa B signaling by IFN-gamma.