Lipopolysaccharide-induced tumor necrosis factor-alpha promoter activity is inhibitor of nuclear factor-kappaB 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-kappaB (NF-kappaB). We examined the signaling pathways involved in the regulation of NF-kappaB that lead to TNF-alpha promoter activity. We determined a role for one or both of the recently identified inhibitor of NF-kappaB kinases, IkappaB kinase-1 and IkappaB kinase-2, in LPS induction of an NF-kappaB reporter and of TNF-alpha promoter activity. IkappaB kinase activation is one of the earliest signaling events known to be induced by LPS. Furthermore, our results suggest roles for the IkappaB kinases NF-kappaB-inducing kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 in the regulation of IkappaB kinase-2, as well as in LPS-induced TNF-alpha transcription.
Swantek
J L
JL
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9041, USA.
Christerson
L
L
Cobb
M H
MH
D000818:Animals; D002460:Cell Line; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D000097782:NF-kappaB-Inducing Kinase
D008070:Lipopolysaccharides; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase