Roles of IKK-β, IRF1, and p65 in the Activation of Chemokine Genes by Interferon-γ

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Abstract
Activation of chemokine genes in response to interferon (IFN)-γ or NF-κB is an important aspect of inflammation. Using the chemokine gene ip-10 in mouse embryonic fibroblast cells as an example, we show that the response to IFN-γ is long lasting but secondary: initial STAT1 activation drives IRF1 synthesis, and IRF1 then binds to IFN-stimulated regulatory elements (ISREs) in the ip-10 promoter. The promoters of most IKK-β-dependent IFN-stimulated genes (ISGs) also contain ISREs. In response to IFN-γ, inhibitor of NF-κB (IκB) kinase β (IKK-β) is required to activate both newly synthesized IRF1 and the p65 subunit of NF-κB, which contributes to ip-10 expression by binding to κB sites in the ip-10 promoter, with little or no activation of classical NF-κB. In contrast to IFN-γ, IL-1β induces ip-10 expression rapidly but transiently, by activating classical NF-κB and increasing the synthesis of IRF1. Together, IL-1β and IFN-γ induce ip-10 synergistically. IFN-γ does not affect the transient activation of classical NF-κB by IL-1β and synergistic induction of ip-10 expression by IFN-γ and IL-1β occurs even after the activation of classical NF-κB has returned to basal levels. Therefore, IKK-β has a novel role in IFN-γ-dependent activation of chemokine gene expression through its activation of IRF1 and p65.

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