Lipopolysaccharide-induced tumor necrosis factor-alpha promoter activity is inhibitor of nuclear factor-kappa B kinase-dependent

The adverse effects of lipopolysaccharide (LPS) are primarily mediated by t umor necrosis factor-alpha (TNF-alpha). TNF-alpha production by LPS-stimula ted macrophages is regulated both transcriptionally and post-transcriptiona lly. Transcriptional regulation of the TNF-alpha gene is dependent on nucle ar 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 o f NF-kappa B kinases, I kappa B kinase-1 and I kappa B kinase-2, in LPS ind uction of an NF-kappa B reporter and of TNF-alpha promoter activity. I kapp a B kinase activation is one of the earliest signaling events known to be i nduced by LPS. Furthermore, our results suggest roles for the I kappa B kin ases NF-kappa B-inducing kinase and mitogen-activated protein kinase/extrac ellular signal-regulated kinase kinase kinase I in the regulation of I kapp a B kinase-2, as well as in LPS-induced TNF-alpha transcription.