Activation of a subset of genes by IFN-gamma requires IKKbeta but not interferon-dependent activation of NF-kappaB.
Activation of NF-kappaB requires the inhibitor of kappaB (IkappaB) kinase (IKK) complex, which is made up of two functional kinases, IKKalpha and IKKbeta, and the scaffolding protein IKKgamma. 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 IKKalpha and IKKbeta. We show here that the IFN-gamma-induced transcription of IKK-dependent ISGs requires IKKbeta but not IKKalpha. We also identify several additional IKKbeta-dependent ISGs that are induced by IFN-gamma both in MEFs and in RAW 264.7 macrophages. Many have a combination of kappaB and IFN-stimulated response elements (ISRE) in their promoters. Although the IFN-gamma-induced expression of the IKKbeta-dependent gene ip-10 is sensitive to the superrepressor (SR) of IkappaBalpha and requires the p65 subunit of NF-kappaB, IFN-gamma does not activate NF-kappaB. In summary, a distinct subset of IFN-gamma-dependent genes requires some components of the normal pathway of NF-kappaB activation without activation of NF-kappaB signaling by IFN-gamma.
Shultz
David B
DB
Department of Molecular Genetics, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Fuller
John D
JD
Yang
Yonghui
Y
Sizemore
Nywana
N
Rani
M R Sandhya
MR
Stark
George R
GR
D000818:Animals; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D046228:Microarray Analysis; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D018121:Receptors, Cytokine / Q000378:metabolism; D020218:Response Elements; D051996:Transcription Factor RelA / Q000378:metabolism*
D020672:I-kappa B Proteins; C104577:IP10-Mig receptor; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D018121:Receptors, Cytokine; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma; D051550:I-kappa B Kinase