IKKi/IKKepsilon plays a key role in integrating signals induced by pro-inflammatory stimuli.
We report that the product of the inducible gene encoding the kinase known as IKKi/IKKepsilon (IKKi) is required for expression of a group of genes up-regulated by pro-inflammatory stimuli such as bacterial endotoxin (lipopolysaccharide (LPS)). Here, using murine embryonic fibroblasts obtained from mice bearing deletions in IKK2, p65, and IKKi genes, we provide evidence to support a link between signaling through the NF-kappaB and CCAAA/enhancer-binding protein (C/EBP) pathways. This link includes an NF-kappaB-dependent regulation of C/EBPbeta and C/EBPdelta gene transcription and IKKi-mediated activation of C/EBP. Disruption of the NF-kappaB pathway results in the blockade of the inducible up-regulation of C/EBPbeta, C/EBPdelta, and IKKi genes. Cells lacking IKKi are normal in activation of the canonical NF-kappaB pathway but fail to induce C/EBPdelta activity and transcription of C/EBP and C/EBP-NF-kappaB target genes in response to LPS. In addition we show that, in response to LPS or tumor necrosis factor alpha, both beta and delta subunits of C/EBP interact with IKKi promoter, suggesting a feedback mechanism in the regulation of IKKi-dependent cellular processes. These data are among the first to provide insights into the biological function of IKKi.
Scripps Research Institute, La Jolla, California 92037, USA.
Vladimir V
VV
Kravchenko
John C
JC
Mathison
Klaus
K
Schwamborn
Frank
F
Mercurio
Richard J
RJ
Ulevitch
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005246:Feedback; D006801:Humans; D051550:I-kappa B Kinase; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D022762:CCAAT-Enhancer-Binding Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse