IKKi/IKKε plays a key role in integrating signals induced by pro-inflammatory stimuli

Abstract

We report that the product of the inducible gene encoding the kinase known as IKKi/IKKε (IKKi) is required for expression of a group of genes up-regulated by proinflammatory 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-κB and CCAAA/enhancer-binding protein (C/EBP) pathways. This link includes an NF-κB-dependent regulation of C/EBPβ and C/EBPδ gene transcription and IKKi-mediated activation of C/EBP. Disruption of the NF-κB pathway results in the blockade of the inducible up-regulation of C/EBPβ, C/EBPδ, and IKKi genes. Cells lacking IKKi are normal in activation of the canonical NF-κB pathway but fail to induce C/EBPδ activity and transcription of C/EBP and C/EBP-NF-κB target genes in response to LPS. In addition we show that, in response to LPS or tumor necrosis factor α, both β and δ 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.