Lipopolysaccharide-induced tumor necrosis factor-α promoter activity is inhibitor of nuclear factor-κB kinase-dependent

The adverse effects of lipopolysaccharide (LPS) are primarily mediated by tumor necrosis factor-α (TNF-α). TNF-α production by LPS-stimulated macrophages is regulated both transcriptionally and post-transcriptionally. Transcriptional regulation of the TNF-α gene is dependent on nuclear factor- κB (NF-κB). We examined the signaling pathways involved in the regulation of NF-κB that lead to TNF-α promoter activity. We determined a role for one or both of the recently identified inhibitor of NF-κB kinases, IκB kinase- 1 and IκB kinase-2, in LPS induction of an NF-κB reporter and of TNF-α promoter activity. IκB kinase activation is one of the earliest signaling events known to be induced by LPS. Furthermore, our results suggest roles for the IκB kinases NF-κB-inducing kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 in the regulation of IκB kinase-2, as well as in LPS-induced TNF-α transcription.