Lipopolysaccharide-induced Tumor Necrosis Factor-α Promoter Activity Is Inhibitor of Nuclear Factor-κB Kinase-dependent

• Published in: The Journal of biological chemistry Vol. 274; no. 17; pp. 11667 - 11671
• Main Authors: Swantek, Jennifer L., Christerson, Lori, Cobb, Melanie H.
• Format: Journal Article
• Language: English
• Published: 23.04.1999
• ISSN: 0021-9258
• DOI: 10.1074/jbc.274.17.11667

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 1 in the regulation of I Kappa B kinase-2, as well as in LPS- induced TNF- alpha transcription.