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