Activation of a Subset of Genes by IFN- γ Requires IKK β but Not Interferon-Dependent Activation of NF- κ B

Abstract

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