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J Biol Chem, Vol. 274, Issue 17, 11667-11671, April 23, 1999
Promoter
Activity Is Inhibitor of Nuclear Factor-
B
Kinase-dependent
From the Department of Pharmacology, University of Texas
Southwestern Medical Center, Dallas, Texas 75235-9041
The adverse effects of lipopolysaccharide (LPS)
are primarily mediated by tumor necrosis factor-
(TNF-). TNF-
production by LPS-stimulated macrophages is regulated both
transcriptionally and post-transcriptionally. Transcriptional
regulation of the TNF- gene is dependent on nuclear factor-
B
(NF-B). We examined the signaling pathways involved in the
regulation of NF-B that lead to TNF- promoter activity. We
determined a role for one or both of the recently identified inhibitor
of NF-B kinases, IB kinase-1 and IB kinase-2, in LPS induction
of an NF-B reporter and of TNF- promoter activity. IB kinase
activation is one of the earliest signaling events known to be induced
by LPS. Furthermore, our results suggest roles for the IB kinases
NF-B-inducing kinase and mitogen-activated protein
kinase/extracellular signal-regulated kinase kinase kinase 1 in the
regulation of IB kinase-2, as well as in LPS-induced TNF- transcription.
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