Roles of IKK-beta, IRF1, and p65 in the activation of chemokine genes by interferon-gamma.
Activation of chemokine genes in response to interferon (IFN)-gamma or NF-kappaB 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-gamma 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-beta-dependent IFN-stimulated genes (ISGs) also contain ISREs. In response to IFN-gamma, inhibitor of NF-kappaB (IkappaB) kinase beta (IKK-beta) is required to activate both newly synthesized IRF1 and the p65 subunit of NF-kappaB, which contributes to ip-10 expression by binding to kappaB sites in the ip-10 promoter, with little or no activation of classical NF-kappaB. In contrast to IFN-gamma, IL-1beta induces ip-10 expression rapidly but transiently, by activating classical NF-kappaB and increasing the synthesis of IRF1. Together, IL-1beta and IFN-gamma induce ip-10 synergistically. IFN-gamma does not affect the transient activation of classical NF-kappaB by IL-1beta and synergistic induction of ip-10 expression by IFN-gamma and IL-1beta occurs even after the activation of classical NF-kappaB has returned to basal levels. Therefore, IKK-beta has a novel role in IFN-gamma-dependent activation of chemokine gene expression through its activation of IRF1 and p65.
Shultz
David B
DB
Department of Molecular Genetics, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Rani
M R Sandhya
MR
Fuller
John D
JD
Ransohoff
Richard M
RM
Stark
George R
GR
D000818:Animals; D054357:Chemokine CXCL10 / Q000235:genetics; D018925:Chemokines / Q000235:genetics*; D051550:I-kappa B Kinase / Q000378:metabolism*; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation
D054357:Chemokine CXCL10; D018925:Chemokines; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D053583:Interleukin-1beta; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D007371:Interferon-gamma; D051550:I-kappa B Kinase